Conformational control in proton sources for enantioselective protonation of samarium enolate derived from α-methoxy-substituted ketones

Article abstract of DOI:10.1055/s-1998-1746

High enantioselectivity is achieved in the asymmetric protonation of samarium enolate, regioselectively generated by SmI₂-mediated reduction of 2-methoxy-substituted cydohexanones using achiral diamine- or pro-atropisomeric 2,2′-biphenol-derived chiral diols as proton sources by virtue of the conformational control.

Full text of DOI:10.1055/s-1998-1746

June 1998
SYNLETT
607
Conformational Control in Proton Sources for Enantioselective Protonation of Samarium
Enolate Derived from α-Methoxy-Substituted Ketones
*
Koichi Mikami, Makoto Yamaoka, and Akihiro Yoshida
Department of Chemical Technology, Tokyo Institute of Technology, Meguro-ku, Tokyo 152, Japan
*
Yutaka Nakamura, Seiji Takeuchi, and Yoshiaki Ohgo
Niigata College of Pharmacy, 5-13-2 Kamishin'ei cho, Niigata 950-21, Japan
Received 17 March 1998
Abstract: High enantioselectivity is achieved in the asymmetric
protonation of samarium enolate, regioselectively generated by SmI -
2
mediated reduction of 2-methoxy-substituted cyclohexanones using
achiral diamine- or pro-atropisomeric 2,2'-biphenol-derived chiral diols
as proton sources by virtue of the conformational control.
Enantioselective protonations of metal enolates with chiral proton
sources such as alcohols, phenols and metal complexes thereof are a
useful method to synthesize chiral carbonyl compounds or carboxylic
1,2
acid derivatives bearing a stereogenic center at the α-position. We
have reported the enantioselective protonation of samarium enolates
3
which are regioselectively generated by SmI -mediated reaction of the
2
α-hetero-substituted cyclohexanones (1) bearing an α-aryl substituent,
using a chiral binaphthol-derived C -symmetric diol as a proton
2
4,5,
source. We now wish to report that chiral diol proton sources derived
from achiral diamine or pro-atropisomeric biphenol are quite effective
by virtue of their conformational control in enantioselective protonation
of samarium enolate generated from the α-methoxy-substituted ketones
(Scheme 1).
Scheme 1
Typical experimental procedure is as follows: To a solution of α-
alkoxyketone in dry tetrahydrofuran was added a solution of SmI in
2
tetrahydrofuran. To the reaction mixture was added a chiral proton
6
source. After stirring for 30 min, usual work-up followed by
purification by silica-gel column chromatography afforded the ketone in
80-90% yield. The enantiomeric excess of the ketone is determined by
chiral HPLC analysis (DAICEL CHIRALCEL OD-H). The results thus
obtained were summarized in Tables 1-3.
Inspection of Table 1 reveals the characteristic features of the present
asymmetric protonation. 5-Membered chelate with samarium is better
than the 6-membered counterpart in terms of the enantioselectivity
(entries 1 vs. 2). Such rigid 5-membered chelate structure and sterically
demanding substituent at the carbinol carbon is preferable to give high
enantioselectivity. Therefore, pantoyl lactone provides higher selectivity
(entries 2 vs. 3). Tridentate ligand to form bicyclic 5,5-members
provides an improved selectivity up to 67% ee (entry 4). Furthermore, a
tetradentate proton source to form 5,5,5-tricyclic chelates provides
further increased selectivity than similar tetradentate proton sources to
form 6,5,5-chelates or facial-type chelates (entries 6 vs. 7 and 8).
However, pentacoordinated proton source is less effective than the
tetradentate proton source (entries 9 vs. 10).
product in the mixture undergoes racemization over more than 30 min at
room temperature (entries 6 and 13 vs. 14), presumably because of a
samarium alkoxide even in the case with pantoyl lactone (entries 3 vs.
11).
Further examination of similar meridional-type chelating proton sources
highlights the conformational control over the achiral diamine tether in
3 for enantioselective protonation (Figure 1). Co-operative effect of the
sterically demanding N-benzyl group and the phenyl substituent at the
carbinol carbon would be operative for the high level of
enantioselectivity (B over C) in view of the low enantioselectivity
obtained with
a
tetraphenyl proton source to fix the N-benzyl
7
conformation (D) because of the Pitzer strain (entries 17 and 9 vs. 6).
We have further found that short reaction time within 30 min is the key
to obtain the higher enantioselectivity with diol (3) or pantoyl lactone
(Table 2). Unfortunately however, the diol (3) does not work well as a
This conformational control could be further extented to achiral but
8
pro-atropisomeric
2,2'-biphenol tether in 4 for enantioselective
6
chiral proton source at low temperature (entries 6 vs. 15). The ketone
protonation (B' and E).

608
LETTERS
SYNLETT
Figure 2
using a (R)-binaphthol-derived C -symmetric diol proton source (entries
2
20 and 21 vs. 23 and 24) and much higher than with (S)-binaphthol-
derived C -symmetric diol (entries 20 vs. 22).
2
In summary, we have disclosed herein that high enantioselectivity is
achieved in the asymmetric protonation of samarium enolate,
regioselectively generated by SmI -mediated reduction of 2-methoxy-
2
substituted cyclohexanones using achiral diamine- or pro-atropisomeric
biphenol-derived chiral diols as proton sources by virtue of the
conformational control.
Acknowledgment: The authors wish to express their thanks to NITTO
KAGAKU KOGYO Co., Ltd. for the generous gift of (R)-styrene oxide.
References and Notes:
1.
Reviews: (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) Fehr, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2566.
(e) Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 411.
2.
For a catalytic enantioselective protonation: (a) Fehr, C.; Stempf, I.;
Galindo, J. Angew. Chem., Int. Ed. Engl. 1993, 32, 1044. (b) Fehr, C.;
Galindo, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1888.
(c) Yanagisawa, A.; Kikuchi, T.; Watanabe, T.; Kuribayashi, T.;
Yamamoto, H. Synlett 1995, 372. (d) Nakamura Y.; Takeuchi, S.;
Ohira, A.; Ohgo, Y. Tetrahedron Lett. 1996, 37, 2805. (e) Ishihara,
K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc.
1996,
118, 12854. (f) Muzart, J.; Henin, F.; Aboulhoda, S. J.
1997, , 381. (g) Sugiura, M.; Nakai, T.
Tetrahedron: Asymmetry
8
1997, , 2366. (h) Riviere, P.; Koga,
36
Angew. Chem., Int. Ed. Engl.
K. Tetrahedron Lett. 1997, 38, 7589.
3.
Reviews: (a) Kagan, H. B.; Namy, J. L. Tetrahedron 1986, 42, 6573.
(b) Inanaga, J. J. Synth. Org. Chem., Jpn. 1989, 47, 200. (c) Kagan,
H. B. New J. Chem. 1990, 14, 453. (d) Molander, G. A.; Harris, C. R.
1996, , 307.
96
Chem. Rev.
4.
5.
Nakamura, Y.; Takeuchi, S.; Ohgo, Y.; Yamaoka, M.; Yoshida, A.;
Mikami, K. Tetrahedron Lett. 1997, 38, 2709.
Molander, et al. have reported that a wide range of α-hetero-
substituted carbonyl compounds are rapidly reduced under mild
conditions by SmI2 in the presence of an achiral proton source such
as methanol. Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51,
1135.
6.
7.
When the reaction was carried out at low temperature, a chiral proton
source was added to the reaction mixture prior to the preparation of
the samarium enolate. Upon addition of a chiral proton source to the
solution of the samarium enolate at –45 °C, the enantiomeric excess
of the product was lower than that obtained at room temperature.
Fuchs, B. "Conformations of Five-Membered Rings" in Topics in
Stereochemistry Vol. 10, Chap. 1, Eliel, E. L.; Allinger, N. L. Eds.,
Wiley: New York, 1978.
Figure 1
8.
9.
Mikami, K.; Matsukawa, S. Nature 1997, 385, 613.
Pro-atropisomeric biphenol-derived proton source (4) is quite effective
Berti, G.; Macchia, B.; Macchia, F.; Monti, L. J. Chem. Soc. (C)
to give an equally high level of enantioselectivity to that obtained by
1971
, 3371.