First catalytic enantioselective proton abstraction using chiral aikoxides

Full text of DOI:10.1021/ja960816t

J. Am. Chem. Soc. 1996, 118, 12483-12484
12483
First Catalytic Enantioselective Proton Abstraction
Using Chiral Alkoxides
Scheme 1
Morad Amadji, J e´ r oˆ me Vadecard,
Jean-Christophe Plaquevent, Lucette Duhamel,* and
Pierre Duhamel
URA CNRS 464 and IRCOF, Facult e´ des Sciences de Rouen
Scheme 2
F-76821 Mont-Saint-Aignan Cedex, France
ReceiVed March 13, 1996
The present work discloses the first reported use of chiral
alkoxides acting as chiral bases in a catalytic enantioselective
proton abstraction; the chosen model reaction leads to enantio-
merically enriched chirons 2 from prochiral dibromo acetals 1
through a highly enantioselective dehydrohalogenation reaction.
A relay system allows the controlled regeneration of an achiral
alkoxide (MeOK) and of a chiral one (potassium N-methyl-
ephedrinate 3(K)).
Asymmetric reactions under the influence of chiral bases have
been the focus of intense research during the last decade. The
first successful approaches were independently disclosed in 1980
1
2
by Whitesell and Felman and by our group. Since this date,
numerous asymmetric reactions using chiral lithium amides have
3
4
been described by us and others thus demonstrating the high
potency of these chiral auxiliaries, able either to discriminate
two enantiotopic protons of a prochiral substrate or to render
enantioselective the addition of an electrophilic reagent to a
Table 1. Catalytic Enantioselective Dehydrohalogenation of 1a-g
with 3(K) as Chiral Alkoxide
prochiral nucleophilic intermediate generated by the chiral base.
MeOH
Catalytic versions have also been reported.4
g,h
As part of our
runa (equiv)
ee (%)b
R
yield (%)
study of chiral bases, we have recently focused on chiral
alkoxides. Thus, we described highly enantioselective dehy-
drobromination reactions leading to axially dissymmetric com-
pounds (ee up to 98%). Nevertheless, these experiments
required the use of an excess of the chiral potassium alkoxide
c
1
2
3
4
0.4
0.2
0.05
0.04
1a tBu
2a not determined
not determined
68 (90)
c
c
83
86 (90)
(90)
not determined
5
c
83
90 (90)
d
>98 (>98)d
c,d
7
5
c
5
6
7
8
9
0.04 1b nPr
0.04 1c iPr
0.04 1d pPhC
0.04 1e pO
0.04 1f Ph
0.04 1g pMeOC H4 2g 79
2b 78
2c 79
2d 81
2e 78
2f 82
77 (79)
(
Scheme 1).
c
65 (65)
In order to achieve this reaction under catalytic conditions,
e
6
H
4
96 (>98)
the key problem was to design a system consisting of an achiral
base (in excess) and of the chiral alkoxide (in catalytic amount)
in which the achiral component would be able to deprotonate
the chiral alcohol but not the prochiral substrate 1.
The reaction was carried out using the following compo-
nents: (i) potassium hydride (excess); (ii) methanol (catalytic
amount); (iii) N-methylephedrine (3(H)) (catalytic amount).
Indeed, KH was able to generate potassium methylate in situ
at low temperature, and the resulting achiral alkoxide entered
in equilibrium with the required potassium ephedrinate 3(K).
e
2
NC
6
H
4
>98 (>98)
e
94 (>98)
e
10
6
>98 (>98)
a
Reaction time: 72 h. Temperature: -80 °C. Experimental
procedure for runs 4-10 is described in ref 8 (KH/MeOH/3(H)/1 )
.5:0.04:0.1:1). b In parentheses, ee obtained using 2.5 equiv of 3(K)
2
instead of the catalytic system. (R)-Configuration was assigned to 2a
c
and 2d according to X-ray analysis (ref 5b, 7). Determined by GC
(
see ref 8). d After one crystallization of the sample of entry 4.
Determined by HPLC (see ref 8).
e
This last reagent gave the expected asymmetric induction in
the dehydrohalogenation of dibromo acetals 1 (Scheme 2, Table
(
1) Whitesell, J. K.; Felman, S. W. J. Org. Chem. 1980, 45, 755-758.
2) Duhamel, L.; Plaquevent, J. C. Tetrahedron Lett. 1980, 21, 2521-
6
(
1
).
Entries 1-4 show the influence of methanol concentration
in the catalytic generation of the chiral alkoxide. The best result
for 1a (run 4 of Table 1, 90% ee, enhanced to 98% by
crystallization) was obtained when using only 0.04 equiv of the
achiral alcohol. This result compares with the similar reaction
carried out with an excess of chiral alkoxide. In entries 5-10
are recorded results obtained using the best catalytic system
KH/MeOH/3(H) 2.5:0.04:0.1 equiv) for the enantioselective
dehydrobromination of 1 having several different substituents
R. High enantioselectivities were obtained for aromatic deriva-
tives 2d-g (94-99% ee, without any crystallization), thus
giving access to a variety of chirons in the 1,3-dioxane series.
We are currently evaluating the potential of these chirons
for further studies in asymmetric synthesis and for the construc-
2
524.
(3) (a) Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, (II),
7
1
5-83. (b) Duhamel, L.; Fouquay, S.; Plaquevent, J. C. Tetrahedron Lett.
986, 27, 4975-4978. (c) Duhamel, L.; Ravard, A.; Plaquevent, J. C.;
Davoust, D. Tetrahedron Lett. 1987, 28, 5517-5520. (d) Duhamel, L.;
Duhamel, P.; Fouquay, S.; Jamal Eddine, J.; Peschard, O.; Plaquevent, J.
C.; Ravard, A.; Solliard, R.; Valnot, J. Y.; Vincens, H. Tetrahedron 1988,
4
4, 5495-5506. (e) Duhamel, L.; Ravard, A.; Plaquevent, J. C. Tetrahe-
5b
dron: Asymmetry 1990, 1, 347-350. (f) Duhamel, L.; Ravard, A.;
Plaquevent, J. C.; Pl e´ , G.; Davoust, D. Bull. Soc. Chim. Fr. 1990, 127,
7
87-797.
(
(
4) For reviews (stoechiometric conditions), see: (a) Cox, P. J.; Simpkins,
8
N. S. Tetrahedron: Asymmetry 1991, 2, 1-26. (b) Simpkins, N. S. Chem.
Ind. 1988, 387-389. (c) Koga, K. Yuki Gosei Kagaku Kyokaishi 1990, 463-
4
75. (d) Waldmann, H. Nachr. Chem. Tech. Lab. 1991, 39, 413-418. (e)
Reed, F. Spec. Chem. 1991, 11, 148-151. (f) Koga, K. In New Aspects of
Organic Chemistry II; Yoshida, Z., Ohshiro, Y., Eds.; Kodansha: Tokyo,
1
992; Chapter 5, pp 67-86. (g) Asami, M.; Ishizaki, T.; Inoue, S.
Tetrahedron: Asymmetry 1994, 5, 793-796. (h) Koga, K.; Shindo, M. J.
Synth. Org. Chem. Jpn 1995, 53, 1021-1032.
(
5) (a) Vadecard, J.; Plaquevent, J. C.; Duhamel, L.; Duhamel P. J. Chem.
(6) Prochiral dibrominated dioxanes 1 were prepared according to the
following: Amadji, M.; Vadecard, J.; Schimmel, U.; Pl e´ , G.; Plaquevent,
J. C. J. Chem. Res., Synop. 1995, 362-363.
Soc., Chem. Commun. 1993, 116-117. (b) Vadecard, J.; Plaquevent, J. C.;
Duhamel, L.; Duhamel, P.; Toupet, L. J. Org. Chem. 1994, 59, 2285-
2
286.
(7) Vadecard, J. Thesis, University of Rouen, France, 1994.
S0002-7863(96)00816-5 CCC: $12.00 © 1996 American Chemical Society

12484 J. Am. Chem. Soc., Vol. 118, No. 49, 1996
Communications to the Editor
Scheme 3
Scheme 4
Finally, the use of the same catalytic system (3(K) as chiral
alkoxide) was extended to the asymmetric synthesis of the
axially dissymmetric acid 6, giving similar results compared to
5
a
those using the chiral base in excess (ee about 65%) (Scheme
).
In conclusion, we have found an unprecedented catalytic
4
system for enantioselective proton abstraction by means of chiral
alkoxides. This finding reinforces the potential of chiral
1
0
alkoxides, chiral bases that are complementary to the better
known chiral lithium amides. Finally, the methodology de-
scribed herein allows the practical synthesis of useful chiral 1,3-
tion of chiral compounds.9 For example, we have already
prepared compounds 4 and 5 by the methodology described in
Scheme 3, without loss of enantiomeric purity.
1
1
dioxanes.
(8) The general experimental procedure is as follows. To a suspension
Acknowledgment. The authors thank the Conseil R e´ gional de
of potassium hydride (2.5 mmol) in THF (8 mL) was added under argon
atmosphere a solution of methanol (0.04 mmol) in THF (0.4 mL) at room
temperature. After cooling at -80 °C, a solution of compound 1 (1 mmol)
and of (1R,2S)-N-methylephedrine 3(H) (0.1 mmol) in THF (2 mL) was
added dropwise. The reaction mixture was kept at -80 °C for 3 days. The
workup and purification procedure for compounds 2a-e was as follows:
the reaction was quenched at -80 °C by aqueous 1 N hydrochloric acid (5
mL). Diethyl ether (5 mL) was then added, and the reaction mixture was
allowed to warm to room temperature. After washing three times with
aqueous 1 N hydrochloric acid, the resulting organic solution was neutralized
by an aqueous saturated solution of sodium hydrogen carbonate and then
dried over magnesium sulfate. After removal of the solvents, the crude
material was chromatographed on silica gel 60 (petroleum ether/diethyl ether
Haute-Normandie for a research grant (M.A.) and Dr. L. Toupet,
(University of Rennes, France) for the determination of crystal
structures.
Supporting Information Available: Spectral and characterization
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JA960816T
(10) Since the first communication from our group regarding the use of
5
a
chiral alkoxides in enantioselective dehydrobromination reactions, some
reports have been published on enantioselective deprotonation of meso
epoxides (mixed amide-alkoxide bases), see: (a) Milne, D.; Murphy, P.
J. J. Chem. Soc., Chem. Commun. 1993, 884-885. (b) Hodgson, D. M.;
Whitherington, J.; Moloney, B. A. Tetrahedron: Asymmetry 1994, 5, 337-
338. (c) Hodgson, D. M.; Whitherington, J.; Moloney, B. A. J. Chem. Soc.,
Perkin Trans. 1 1994, 3373-3377. (d) Hodgson, D. M.; Gibbs, A. M.
Tetrahedron: Asymmetry 1996, 7, 407-408.
)
90:10 for compounds 2a-c; petroleum ether/ethyl acetate ) 90:10 for
compounds 2d,e). The workup and purification procedure for compounds
2
f,g was identical except that the use of hydrochloric acid was avoided
and that all of the washings were an aqueous saturated solution of sodium
hydrogen carbonate. The crude material was chromatographed on silica gel
6
0 using petroleum ether/ethyl acetate ) 90:10 as eluent. The ee values of
compounds 2a-c were determined by GC (Supelco â-dex-120). The ee
values of compounds 2d-g were determined by HPLC (Chiracel OJ,
isopropanol/hexane ) 40:60, flow rate ) 1 mL/mn).
(11) For the use of cyclic acetals in synthesis, see: (a) Frauenrath, H.
Synthesis 1989, 721-734. (b) Enders, D.; Bockstiegel, B. Synthesis 1989,
493-496. (c) Seebach, D.; Lapierre, J. M.; Jaworek, W.; Seiler, P. HelV.
Chim. Acta 1991, 56, 4264-4268.
(9) Amadji, M. Thesis, University of Rouen, France, in preparation. Also,
unpublished results from our group.