2756
J. Am. Chem. Soc. 1996, 118, 2756-2757
Scheme 1
Steric Protection of the Selenium Atom of the
Episelenonium Ion Intermediate To Prevent both
the Racemization of the Chiral Carbon and the
Selenophilic Attack of Carbon Nucleophiles
Akio Toshimitsu,* Katsuhiro Nakano, Takao Mukai, and
Kohei Tamao
Institute for Chemical Research, Kyoto UniVersity
Uji, Kyoto 611, Japan
ReceiVed NoVember 15, 1995
Organic reactions Via the three-membered cyclic episele-
nonium ion intermediate have been widely used in organic
syntheses.1 Still, two basic drawbacks of the episelenonium
ion intermediate remain to be solved. Thus, in the episele-
nonium ion intermediate bearing a phenyl group on the selenium
atom, (1) a chiral carbon present in the three-membered ring
racemizes quite readily during reactions,2 and (2) carbon
nucleophiles such as ketene silyl acetals attack the selenium
atom selectively rather than the carbon atom to give no carbon-
carbon bond formation products.3 We describe herein that these
drawbacks are both overcome by the steric protection of the
selenium atom by the 2,4,6-tri-tert-butylphenyl (TTBP) group.
Our strategy is based on our observation that the rate of
racemization of the chiral carbon in the episelenonium ion
intermediate is highly dependent on the concentration of the
substrates in the Ritter-type reaction. Thus, in the acid-induced
reaction in acetonitrile4 of the chiral alcohol 1b5 bearing the
o-(trifluoromethyl)phenylseleno group on the adjacent carbon
atom (Scheme 1), the enantiomeric excesses6 of the product
amide 3b are better in the reactions at lower concentrations, as
shown in Table 1. The data in Table 1 also show that the reverse
addition,7 namely, addition of the alcohol 1b to a solution of
acid in acetonitrile, affords the amide 3b of better enantiomeric
excesses than does the normal addition, that is, addition of a
solution of acid to a solution of 1b in acetonitrile. It should be
noted that while in the normal addition procedure episelenonium
ion intermediates 2 are formed in the presence of unreacted
starting material 1b, in the reverse addition all starting materials
are converted into the episelenonium ions as added, which must
Table 1. Effect of the Concentrations of the Alcohol 1b on the
Stereospecificity for the Formation of 3b Via 2ba
stereospecificity, %b
conc, mol/L
normal addnc
reverse addnd
0.1
0.004
0.001
9e
45
75
41
91
98
a Carried out using 1b (0.1 mmol) and a mixture of CF3SO3H and
H2O (1 mmol, 1:1 by molar ratio) in acetonitrile at ambient temperature.
b Defined as follows: stereospecificity % ) ((% ee of 3) × 100)/(%
ee of 1). c The solution of the acid was added to the solution of 1b.
d The solution of 1b was added to the solution of the acid. e A
stoichiometric amount (0.1 mmol) of CF3SO3H and H2O was used.
react with acetonitrile to form the amides. These results reveal
that the racemization does not occur during the formation of
the episelenonium ion intermediate Via the bimolecular reaction
of the arylseleno-substituted alcohol and the acid and during
its reaction with nitrile but would be induced by selenophilic
attack on the selenium atom of the episelenonium ion intermedi-
ate by the excess arylseleno-substituted alcohol.8 This hypoth-
esis prompted us to prove that the racemization is suppressed
by the steric protection of the selenium atom from selenophilic
attack.
Indeed, among several arylseleno groups examined, the
alcohol bearing 2,4,6-tri-tert-butylphenylseleno (TTBPSe) group9,10
1e has been found to afford the amide 3e6 without loss of optical
purity; 2,6-xylyl (1c) and 2,4,6-triisopropylphenyl (1d) groups
(28% and 33% stereospecificity)11 were far less effective than
the TTBP group. Worthy of note is that the TTBP group allows
the reaction to proceed with complete stereospecificity even at
higher concentration (0.1 mol/L) favorable for racemization.
This result clearly shows that the bulky TTBPSe group prevents
completely the racemization of the chiral carbon in the epise-
lenonium ion intermediate, thus providing strong evidence for
our hypothesis.
(1) For recent examples, see (a) Wirth, T. Angew. Chem., Int. Ed. Engl.
1995, 34, 1726. (b) Fujita, K.; Murata, K.; Iwaoka, M.; Tomoda, S. J. Chem.
Soc., Chem. Commun. 1995, 1641. (c) De´ziel, R.; Malenfant, E. J. Org.
Chem. 1995, 60, 4660. (d) Lipshutz, B. H.; Gross, T. J. Org. Chem. 1995,
60, 3572. (e) Fukuzawa, S.; Kasugahara, Y.; Uemura, S. Tetrahedron Lett.
1994, 35, 9403. (f) De´ziel, R.; Goulet, S.; Grenier, L.; Bordeleau, J.; Bernier,
J. J. Org. Chem. 1993, 58, 3619. (g) Tiecco, M.; Testaferri, L.; Tingoli,
M.; Bagnoli, L.; Santi, C. J. Chem. Soc., Chem. Commun. 1993, 637. (h)
Kang, S. H.; Lee, S. B. Tetrahedron Lett. 1993, 34, 1955. (i) Mihelich, E.
D.; Hite, G. A. J. Am. Chem. Soc. 1992, 114, 7318. (j) Lipshutz, B. H.;
Barton, J. C. J. Am. Chem. Soc. 1992, 114, 1084. (k) Mihelich, E. D. J.
Am. Chem. Soc. 1990, 112, 8995 and references cited therein.
(2) Toshimitsu, A.; Ito, M.; Uemura, S. J. Chem. Soc., Chem. Commun.,
1989, 530. For the epimerization of the chiral ring carbon in a diastereomeric
episelenonium ion intermediate, see ref 1k.
(3) Alexander, R. P.; Paterson, I. Tetrahedron Lett. 1983, 24, 5911.
Successful examples of the carbon-carbon bond formation Via the
episelenonium ion intermediate have been limited to certain intramolecular
reactions using olefins as a carbon nucleophile: (a) Toshimitsu, A.;
Kusumoto, M.; Tanimoto, S. Bull. Inst. Chem. Res., Kyoto UniV. 1992, 70,
270. (b) Ley, S. V.; Lygo, B.; Morins, H.; Morton, J. A. J. Chem. Soc.,
Chem. Commun. 1982, 1251. (c) Toshimitsu, A.; Uemura, S.; Okano, M.
J. Chem. Soc., Chem. Commun. 1982, 87. (d) Kametani, T.; Kurobe, H.;
Nemoto, H. J. Chem. Soc., Perkin Trans. 1 1982, 1085, and references
cited therein.
In addition to prevention of the racemization, the steric
protection by the TTBP group of the selenium atom has been
(4) Toshimitsu, A.; Hayashi, G.; Terao, K.; Uemura, S. J. Chem. Soc.,
Perkin Trans. 1 1986, 343.
(5) The chiral alcohols were prepared by the ring opening of chiral
oxiranes by sodium areneselenolates, generated by the reaction of diaryl
diselenide with NaBH4.
(6) The enantiomeric excesses of 3a-e were determined by HPLC
analyses using chiral columns (Chiralcel OD (Daicel) for 3a, 3b, and 3e
and Chiralpak AD (Daicel) for 3c and 3d).
(7) Total yields and isomer ratios were not affected by the mode of the
addition.
(8) The precise mechanism of this reaction has not yet been clarified.
(9) Rundel, W. Chem. Ber. 1968, 101, 2956. du Mont, W. W.; Kubiniok,
S.; Peters, K.; von Schnering,H.-G. Angew. Chem., Int. Ed. Engl. 1987,
26, 780.
(10) Pearson, D. E.; Frazer, M. G.; Frazer, V. S.; Washburn, L. C.
Synthesis 1976, 621.
(11) These reactions were carried out at the concentration of 0.001 mol/L
using the reverse addition.
0002-7863/96/1518-2756$12.00/0 © 1996 American Chemical Society