Asymmetric protonation of ketone enolates using chiral β- hydroxyethers: Acidity-tuned enantioselectivity

Article abstract of DOI:10.1021/jo0498258

New chiral hydroxyethers 1a-f were prepared for asymmetric protonation of achiral enolates prepared from prochiral ketones. The enantioselectivity of protonation was highly dependent upon the acidity of the chiral alcohols, the highest enantioselectivity

Full text of DOI:10.1021/jo0498258

Asym m etr ic P r oton a tion of Keton e
En ola tes Usin g Ch ir a l â-Hyd r oxyeth er s:
Acid ity-Tu n ed En a n tioselectivity
B. Moon Kim,* Hyunwoo Kim, Woosung Kim,
Keun Young Im, and J in Kyoon Park
School of Chemistry, Seoul National University,
Seoul, 151-747, South Korea
F IGURE 1. Asymmetric protonation of enolates using various
chiral alcohols as proton donors.
kimbm@snu.ac.kr
Received J anuary 30, 2004
Abstr a ct: New chiral hydroxyethers 1a -f were prepared
for asymmetric protonation of achiral enolates prepared from
prochiral ketones. The enantioselectivity of protonation was
highly dependent upon the acidity of the chiral alcohols, the
highest enantioselectivity (90% ee) being achieved with 3,5-
dichloro-substituted â-hydroxyether 1c. A salt-free enolate
generated from trimethylsilyl enol ether 4 provided product
of the highest ee. Unlike other reagents, chloro-substituted
alcohols provided almost consistent enantioselections through-
out the reaction temperatures examined (-25 to -98 °C).
Protonation of other aromatic ketones showed selectivity
similar to that of 2-methyl-1-tetralone.
Enantioselective protonation is one of the most efficient
approaches for obtaining optically active R-substituted
carbonyl compounds since a chiral proton source can be
recovered and reused.1 Many stoichiometric and catalytic
chiral proton donors for enantioselective protonation of
prochiral enolates have been developed. Among many
reagents used for the asymmetric protonation, chiral
alcohols and amines have been employed most fre-
quently. As depicted in Figure 1, most chiral alcohols
contain various functional groups such as carbonyl (A),2-5
amino (B),6-8 sulfinyl (C),9,10 and selenoxy (D)11 groups
adjacent to the hydroxyl moiety to assist in better
chelation of the metal from the enolate. Among these,
the sulfinyl directing group (C) has proven to be most
effective, allowing for exceedingly enantioselelctive (up
to 99% ee’s) protonation.9,10 It appears that these groups
F IGURE 2. Chiral hydroxyethers 1a -f and 2 and Molecular
modeling of (S,S)-1a . Geometry was optimized at PM3 using
the PC Spartan Pro program.
coordinate to the metal of the enolate and discriminate
two enantiotopic faces in the protonation step. However,
proton donors composed of chiral â-hydroxy ethers (E)
are rare,12 presumably due to the common acceptance
that the ether functionality is not effective as a ligand
for metals.
(1) For recent reviews, see: (a) Eames, J .; Weerasooriya, N. Tetra-
hedron: Asymmetry 2001, 12, 1-24. (b) Yanagisawa, A.; Yamamoto,
H. In Comprehensive Asymmetric Catalysis; J acobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 1999; pp 1295. (c) Yanag-
isawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 411. (d) Fehr, C.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2566.
(2) Matsumoto, K.; Ohta, H. Tetrahedron Lett. 1991, 32, 4729.
(3) (a) Gerlach, U.; Haubenreich, T.; Hu¨nig, S. Chem. Ber. 1994,
127, 1969. (b) Gerlach, U.; Haubenreich, T.; Hu¨nig, S. Chem. Ber. 1994,
127, 1981. (c) Gerlach, U.; Haubenreich, T.; Hu¨nig, S.; Klauzer, N.
Chem. Ber. 1994, 127, 1989.
(4) (a) Cavelier, F.; Gomez, S.; J acquier, R.; Verducci, J . Tetrahe-
dron: Asymmetry 1993, 4, 2501. (b) Cavelier, F.; Gomez, S.; J acquier,
R.; Verducci, J . Tetrahedron Lett. 1994, 35, 2891.
(5) Fuji, K.; Kawabata, T.; Kuroda, A. J . Org. Chem. 1995, 60, 1914.
(6) Fujihara, H.; Tomioka, K. J . Chem. Soc., Perkin Trans. 1 1999,
2377.
(7) (a) Fehr, C.; Stempf, I.; Galindo, J . Angew. Chem., Int. Ed. Engl.
1993, 32, 1042. (b) Fehr, C.; Galindo, J . Helv. Chim. Acta 1995, 78,
539. (c) Fehr, C.; Galindo, J . Angew. Chem., Int. Ed. Engl. 1994, 33,
1888.
(8) Toussaint, O.; Capdevielle, P.; Maumy, M. Tetrahedron Lett.
1987, 28, 539.
(9) (a) Kosugi, H.; Hoshino, K.; Uda, H. Tetrahedron Lett. 1997, 38,
6861. (b) Kosugi, H.; Abe, M.; Hatsuda, R.; Uda, H.; Kato, M. Chem.
Commun. 1997, 1857.
We envisioned that if both the alcohol and the ether
oxygen atoms of 1a 13 are employed to bind a metal, a
(10) (a) Asensio, G.; Aleman, P. A.; Domingo, L. R.; Medio-Simo´n,
M. Tetrahedron Lett. 1998, 39, 3277. (b) Asensio, G.; Aleman, P.;
Cuenca, A.; Gil, J .; Medio-Simo´n, M. Tetrahedron: Asymmetry 1998,
9, 4073. (c) Asensio, G.; Aleman, P.; Gil, J .; Domingo, L. R.; Medio-
Simo´n, M. J . Org. Chem. 1998, 63, 9342. (d) Asensio, G.; Cuenca, A.;
Gavin˜a, P.; Medio-Simo´n, M. Tetrahedron Lett. 1999, 40, 3939.
(11) (a) Takahashi, T.; Nakao, N.; Koizumi, T. Chem. Lett. 1996,
207. (b) Takahashi, T.; Nakao, N.; Koizumi, T. Tetrahedron: Asym-
metry 1997, 8, 3293.
(12) Chiral oligo(hydroxy ethers) have been used in the protonation
of samarium enolates generated from SmI2-mediated reactions of
ketone derivatives. See: (a) Takeuchi, S.; Miyoshi, N.; Ohgo, Y. Chem.
Lett. 1992, 551. (b) Takeuchi, S.; Ohira, A.; Miyoshi, N.; Mashio, H.;
Ohgo, Y. Tetrahedron: Asymmetry 1994, 5, 1763. (c) Nakamura, Y.;
Takeuchi, S.; Ohgo, Y.; Yamaoka, M.; Yoshida, A.; Mikami, K.
Tetrahedron Lett. 1997, 38, 2709. (d) Mikami, K.; Yamaoka, M.;
Yoshida, A. Synlett 1998, 607. (e) Takeuchi, S.; Nakamura, Y.; Ohgo,
Y.; Curran, D. P. Tetrahedron Lett. 1998, 39, 8691. (f) Nakamura, Y.;
Takeuchi, S.; Ohgo, Y.; Yamaoka, M.; Yoshida, A.; Mikami, K.
Tetrahedron 1999, 55, 4595. (g) Nakamura, Y.; Takeuchi, S.; Ohgo,
Y.; Curran, D. P. Tetrahedron 2000, 56, 351.
(13) Kim, B. M.; Park, J . K. Bull. Kor. Chem. Soc. 1999, 20, 744.
10.1021/jo0498258 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/30/2004
5104
J . Org. Chem. 2004, 69, 5104-5107

TABLE 1. Asym m etr ic P r oton a tion of th e En ola te
Gen er a ted fr om En ol Acetete 3 Usin g MeLi in th e
P r esen ce of Ch ir a l â-Hyd r oxy Eth er 1a or 2 a t Va r iou s
Tem p er a tu r esa
TABLE 3. Effect of Ad d itives in Asym m etr ic
P r oton a tion fr om En ola tes Gen er a ted fr om 3 or 4a
enolate
source
temp
(°C)
salts present
or added
% ee of ketone
entry
(S)-5
entry
proton source
temp (°C)
% ee of (S)-5
1
2
3
4
5
3
3
3
4
4
-78
-78
-42
-78
-78
LiOtBu
72
24
14
81
75
LiOtBu/LiBr
LiOtBu/LiBr
none
1
2
3
4
5
6
(S,S)-2
-78
0
-25
-42
-78
-98
28
46
67
71
72
56
(S,S)-1a
(S,S)-1a
(S,S)-1a
(S,S)-1a
(S,S)-1a
LiBr
a
MeLi in diethyl ether was added to the enolate precursor in
dichloromethane.
a
MeLi in diethyl ether was added to the enol acetate in
dichloromethane.
enantioselection (78% ee, entry 3). Even though 1b is
similar in structure to 1c, protonation with 1b proceeded
with strikingly low enantioselectivity (39% ee, entry 2).
This strongly indicates that the asymmetric protonation
is closely related to the acidity of the proton donor
alcohol.10c,16
TABLE 2. Asym m etr ic P r oton a tion of En ola te
Gen er a ted fr om En ol Aceta te 3 Usin g MeLi a t -78 °Ca
entry
proton source
% ee of ketone (S)-5
1
2
3
(S,S)-1a
(S,S)-1b
(S,S)-1c
72
39
78
The presence of metal salts has been known to change
the enolate structure,17 and improved enantioselectivities
have often been observed with added metal salts such
as lithium in asymmetric protonation.10,18 To examine the
effect of lithium salts in our protonation, reactions were
examined in the presence/absence of LiBr as outlined in
Table 3. Contrary to the previously reported cases, the
addition of lithium bromide to the enolate generated from
10 resulted in a precipitous drop of the enantioselectivity
regardless of reaction temperature (entries 2 and 3, Table
3). Since the generation of lithium enolate from the enol
acetate 3 is inevitably accompanied with lithium tert-
butoxide, also a lithium salt, we examined the reaction
of salt-free lithium enolate. For this purpose, the silyl
enol ether 4 was selected as a precursor for the genera-
tion of the enolate. As can be seen in Table 3, protonation
of the enolate generated from 4 proceeded with the
highest enantioselectivity, yielding product of 81% ee
(entry 4). However, addition of lithium bromide to the
salt-free enolate had a deleterious effect on enantiose-
lectivity (entry 5).
a
MeLi in diethyl ether was added to the enol acetate in
dichloromethane.
pseudo-C2-symmetric alignment could be constructed as
shown in Figure 2. This conformational rigidity may be
exploited in asymmetric protonation of prochiral enolates.
It is also of note that, by changing substituents at the
phenyl ring connected to the carbinol, various steric and
electronic influences on the reaction enantioselectivity
could be examined. Herein we report on the efficient
asymmetric protonation of lithium enolates generated
from R-substituted ketone derivatives employing novel
chiral â-hydroxyethers 1a -f.
Synthesis of â-hydroxy ether analogues equipped with
various substituents (1b-f) has been accomplished ac-
cordingly to the reported method.13 As a control experi-
ment, protonation of an enolate prepared from enol
acetate 3 using (S,S)-2-methoxy-1,2-diphenyl-ethanol 214
was carried out, and ketone (S)-5 of only 28% ee was
obtained (Table 1, entry 1). The low enantioselectivity
might be due to a large degree of freedom around the
acyclic ether moiety of compound 2. When the conforma-
tionally constrained cyclic ether 1a was employed, how-
ever, a significant improvement of enantioselection was
observed as summarized in Table 1. It is interesting to
note that, as the reaction temperature was lowered, the
enantioselectivity of the protonation using 1a increased,
peaking at -78 °C (entry 5), and then decreased as the
temperature was decreased further.15
To examine the effect of the reaction media on enan-
tioselectivity, reactions in various solvents have been
carried out, and the results are summarized in Table 4.
The enantioselection was found to be extremely sensitive
to the solvents, and the best result was achieved when
the reaction was carried out in dichloromethane using
MeLi in ether (entry 1).
Having established the best reaction conditions for the
protonation using chiral hydroxyether 1a , we examined
(16) (a)Vedejs, E.; Lee, N. J . Am. Chem. Soc. 1995, 117, 891. (b)
Vedejs, E.; Kruger, A. W. J . Org. Chem. 1998, 63, 2792. (c) Vedejs, E.;
Kruger, A. W.; Suna, E. J . Org. Chem. 1999, 64, 7863.
Then we examined three electronically dissimilar
chiral â-hydroxy ethers 1a -c. As summarized in Table
2, when the reactions were carried out at -78 °C, the
3,5-dichloro-substituted alcohol 1c exhibited the best
(17) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624.
(18) (a) Murakata, M.; Nakajima, M.; Koga, K. Chem. Commun.
1990, 1657. (b) Yasukata, T.; Koga, K. Tetrahedron: Asymmetry 1993,
4, 35. (c) Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K.
J . Am. Chem. Soc. 1994, 116, 8829. (d) Riviere, P.; Koga, K. Tetrahe-
dron Lett. 1997, 38, 7589. (e) Murakata, M.; Yasukata, T.; Aoki, T.;
Nakajima, M.; Koga, K. Tetrahedron 1998, 54, 2449. (f) Imai, M.;
Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K. Tetrahedron 2000,
56, 179. (g) Yamashita, Y.; Emura, Y.; Odashima, K.; Koga, K.
Tetrahedron Lett. 2000, 41, 209. (h) Yanagisawa, A.; Kikuchi, T.;
Yamamoto, H. Synlett 1998, 174. (i) Yanagisawa, A.; Kikuchi, T.;
Kuribayashi, T.; Yamamoto, H. Tetrahedron 1998, 54, 10253.
(14) Tomioka, K.; Wang, L.-F.; Komine, N.; Nakai, T. Tetrahedron
Lett. 1999, 40, 6813.
(15) Similar tendencies of increased enantioselection at lower tem-
peratures were previously reported. See: (a) Aboulhoda, S. J .; Reiners,
I.; Wilken, J .; He´nin, F.; Martens, J .; Muzart, J . Tetrahedron: Asym-
metry 1998, 9, 1847. (b) He´nin, F.; Le´tinois, S.; Muzart, J . Tetrahe-
dron: Asymmetry 2000, 11, 2037.
J . Org. Chem, Vol. 69, No. 15, 2004 5105

TABLE 4. Solven t Effects on th e P r oton a tion of
En ola tes Gen er a ted fr om Silyl En ol Eth er 4 Usin g
â-Hyd r oxyeth er 1a or 1c
TABLE 5. Asym m etr ic P r oton a tion of a Sa lt-F r ee
En ola te Gen er a ted fr om Silyl En ol Eth er 4 Usin g
â-Hyd r oxyeth er 1a -f or 2 a t Va r iou s Tem p er a tu r es
proton
donor
temp
(°C)
solvent
% ee of ketone
entry
(MeLi/reaction)a
(S)-5
1
2
3
4
5
(S,S)-1a
(S,S)-1a
(S,S)-1c
(S,S)-1a
(S,S)-1a
-78
-78
-78
-42
-25
Et2O/CH2Cl2
Et2O/toluene
Et2O/toluene
Et2O/Et2O
81
30
72
45
2
proton
donora
conversionb
(%)
% ee of ketone
THF/THF
entry
temp (°C)
(S)-5
a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
(S,S)-2
-78
-98
-78
-42
-25
-98
-78
-42
-25
-98
-78
-78
-42
-25
-98
-78
-42
-25
-98
-78
-42
-25
-98
-78
-42
-25
90c
90
3
70
81
73
52
43
56
38
64
88
90
-90e
90
88
74
77
75
78
84
82
70
78
72
79
85
77
MeLi in the first solvent was added to the silyl enol ether in
the second solvent.
(S,S)-1a
(S,S)-1a
(S,S)-1a
(S,S)-1a
(S,S)-1b
(S,S)-1b
(S,S)-1b
(S,S)-1b
(S,S)-1cd
(S,S)-1cd
(R,R)-1c
(S,S)-1cd
(S,S)-1cd
(S,S)-1d
(S,S)-1d
(S,S)-1d
(S,S)-1d
(S,S)-1e
(S,S)-1e
(S,S)-1e
(S,S)-1e
(S,S)-1f
(S,S)-1f
(S,S)-1f
(S,S)-1f
99
64c
93c
96
various chiral hydroxyethers 1a -f at four different
temperatures in order to further examine the influence
of the alcohol’s acidity toward the reaction enantioselec-
tivity. Relative acidities of these halogenated hydroxy-
ethers have been evaluated using computational meth-
ods, and the electrostatic potential, which is believed
to be correlated to the acidity,19 was in the order of 1a ,
1b < 1c, 1d < 1e, 1f.20 As summarized in Table 5, while
protonation using 1a and 1b exhibited variation of
enantioselectivities according to the reaction temperature
(entries 2-5 and 6-9, respectively), reactions using 3,5-
dichlorobenzyl- and 4-chlorobenzyl alcohol derivatives 1c
and 1d showed much improved and almost constant
enantioselectivities regardless of the reaction tempera-
ture (entries 10-14 and 15-18, respectively). Of the two
chlorinated alcohols, 3,5-dichlorinated alcohol 1c pro-
vided the better enantioselection (90% ee, entries 11-
13), and the same magnitude of asymmetric induction
was obtained using either (S,S)-1c or (R,R)-1c at -78
°C. Reactions employing 1d exhibited uniformly lower
(74-78% ees) enantioselection than those using 1c (88-
90% ees), indicating that a steric factor may play a role
in the case of alcohols of similar acidity. To examine the
effect of still more acidic alcohols, we have carried out
reactions using 3,5-bis(trifluoromethyl)benzyl- and 4-(tri-
fluoromethyl)benzyl alcohol derivatives 1e and 1f, re-
spectively. However, neither of the fluorinated alcohols
showed better enantioselection than those obtained with
chloro-substituted hydroxyethers 1c and they exhibited
somewhat fluctuating enantioselectivities according to
the reaction temperature (entries 19-26).
97c
75c
98c
95
87
97
88c
80c
82
97
88
99
89
97
95
76
92
99
97
85
a
Reagents of >99% ee were used unless otherwise noted.
Determined through 1H NMR analysis unless otherwise noted.
b
d
c Determined through HPLC analysis. (S,S)-1c of 96% ee was
used, and the product ee was corrected for the purity of (S,S)-1c.
e Ketone (R)-5 was obtained.
TABLE 6. Asym m etr ic P r oton a tion of Sa lt-F r ee
En ola tes Gen er a ted fr om Silyl En ol Eth er s 6-8 Usin g
â-Hyd r oxyeth er 1c a t -78 °C
A few structurally related aromatic prochiral ketones
have been examined employing 1c under the most
selective asymmetric protonation conditions (Table 6).
Enantioselectivity (87% ee, entry 1) comparable to the
case of 2-methyltetralone was observed in the production
of 2(S)-benzyl-1-tetralone; however, slightly diminished
enantioselectivity (79% ee, entry 2) was obtained in the
protonation of enolates derived from 2-methyl-1-in-
danone. Aliphatic ketones such as 2,2,6-trimethylcyclo-
hexanone turned out to be very poor substrates for
asymmetric protonation using 1c. Almost negligible
asymmetric induction (3% ee) was observed.
a
b
Determined through 1H NMR analysis. Ee values were
determined through HPLC analysis using a Daicel Chiralcel OD-H
column. c Ee value was determined through GC analysis using a
chiral column (SUPELCO, γ-DEX).
As for the transition state model for the asymmetric
protonation using (S,S)-1c, four possible approaches are
postulated as shown in Figure 3. Though lithium enolates
may exist primarily as tetrameric and diametric ag-
gregates in ethereal solution,17 we focused on the mon-
omeric structure to clarify the origin of stereoselectivity.
First, due to the steric interaction between the R-methyl
(19) Tomasi, J . In Chemical Applications of Atomic and Molecular
Electrostatic Potentials; Politzer, P., Truhlar, D. G., Eds.; Plenum: New
York, 1981; p 257.
(20) Energy of a hypothetical proton removal process is given by
the electrostatic potential at the site of the acidic proton in neutral
acid. The values for 1a -f are 44.46, 44.82, 49.22, 49.19, 56.70, and
53.44 kcal/mol, respectively. Calculations were performed at HF/6-
31G** level using the PC Spartan Pro program.
5106 J . Org. Chem., Vol. 69, No. 15, 2004

TABLE 7. Resu lts of th e P r oton a tion of th e En ola te
Der ived fr om 6-Meth oxy-2-m eth yltetr a lon e
ee (%)b of
ee (%)b of 6-methoxy-
proton
donors
temp conversion 2-methyl-
2-methyl-
tetralone
entry
(°C)
(%)a
tetralone
1
2
3
(S,S)-1c
(S,S)-1d
(S,S)-1f
-78
-78
-78
84
85
72
90
78
79
80
92
70
a
b
Determined through 1H NMR analysis. Ee values were
determined through HPLC analysis using a Daicel Chiralcel OD-H
column.
was observed, indicating a repulsive interaction between
the substituted aryl groups due to steric interaction.
In conclusion, we have designed new chiral hydroxy-
ethers 1a -f for asymmetric protonation of achiral eno-
lates prepared from prochiral ketones and the enanti-
oselectivity of reactions employing these hydroxy ethers
were found to be highly dependent upon the acidity of
the chiral alcohols. Compounds 1b and 1c, though similar
in structure, exhibited a dramatic difference in the
enantioselectivity in the protonation of enolate generated
from 3. It was found that a salt-free enolate generated
from trimethylsilyl enol ether 4 provided product of the
highest enantiomeric excess, contrary to the previously
reported systems. Reaction media were also found to
drastically influence the results, and careful selection of
solvents was essential to ensure high enantioselectivity
of the reaction. With a variety of chiral alcohols 1a -f,
product of 90% ee was achieved using 3,5-dichloro-
substituted â-hydroxyether 1c. Reagents with methyl or
trifluoromethyl substituents exhibited fluctuating selec-
tivity depending upon the reaction temperature; however,
chloro-substituted reagents provided almost consistent
enantioselections throughout the reaction temperatures
examined (-25 to -98 °C). Protonations of other aromatic
ketones were examined, and they showed selectivity
similar or slightly inferior to that of 2-methyl-1-tetralone.
Almost negligible asymmetric induction was observed
with aliphatic ketone precursor 8. A transition state
model involving attractive π-π interaction between the
enolate and the chiral proton source is proposed. A ketone
with increased electron density, 6-methoxy-2-methyl-
tetralone, exhibited a preference for chiral alchol 1d
rather than 1c, showing 92% ee with 1d .
F IGURE 3. Four possible transition-state approach models
for the asymmetric protonation of R-methyltetralone using
(S,S)-1c.
group of the enolate and the chiral hydroxy ether, models
A(r e) and D(si) would be more favorable than B(si) and
C(r e). Second, though similar attractive π-π interactions
are considered to exist between the chiral hydroxyether
and the lithium enolate in A(r e) and D(si), due to
electronegative substituents of the chiral hydroxyether,
the chlorinated phenyl ring would decrease the energy
level of the HOMO-LUMO interaction. Consequently,
among the four possible approaches, A(r e) appears to be
the most preferable one, producing the experimentally
observed (S)-ketone. Calculated energy values of HOMO-
LUMO of 1a -d were shown in the order of 1a , 1b > 1c,
1d > 1e, 1f,21 which is in accordance with the previous
calculation of relative acidities.
According to the proposed transition state model, an
increase in the enantioselectivity could be expected from
attractive π-π interaction improving the HOMO-LUMO
interaction. To see if the increased electron density of the
enolate has a positive effect on enantioselectivity, pro-
tonation of an enolate derived from 6-methoxy-2-meth-
yltetralone (9) was examined, and the results are sum-
marized in Table 7.22 When alcohol 1d was used as a
proton source, a significant increase (from 78 to 92% ee)
in enantioselectivity was observed compared to the
reaction of 2-methyltetralone. However, in the case of
protonation using 1c or 1f, decreased enantioselectivity
Ackn owledgm en t. The Foreign Research Aid Schol-
arship from the SBS Foundation for B.M.K. is gratefully
acknowledged. H.W.K., W.S.K., and J .K.P. thank the
BK21 Fellowship from the Ministry of Education, the
Republic of Korea.
(21) Energy levels of HOMO/LUMO of the enolate from ketone 12
and 1a -f. Calculations were performed at the HF/6-31G* level using
the PC Spartan Pro program.
Su p p or tin g In for m a tion Ava ila ble: A reaction scheme
for the preparation of and characterization data for compounds
1a -f, and a representative procedure for asymmetric proto-
nation. This material is available free of charge via the
Internet at http://pubs.acs.org.
(22) Authors thank one of the reviewers for the suggestion on the
experiment with 6-methoxy-2-methyltetralone.
J O0498258
J . Org. Chem, Vol. 69, No. 15, 2004 5107