Asymmetric protonation of lithium enolate of α-amino acid derivatives using chiral Br?nsted acids

Article abstract of DOI:10.1055/s-2001-18754

Chiral alcohols possessing an asymmetric 2-oxazoline ring were synthesized as new chiral Br?nsted acids from tetrahydro-2-furoic acid and (1S, 2R)-2-amino-1,2-diphenylethanol. These alcohols were superior to (S,S)- or (R,R)-imide reported previously as a chiral proton source for enantioselective protonation of lithium enolate of an alanine derivative.

Full text of DOI:10.1055/s-2001-18754

LETTER
1855
Asymmetric Protonation of Lithium Enolate of -Amino Acid Derivatives
using Chiral Brønsted Acids
A
symmetric Proto
k
nation of
L
it
i
E
r
nolate of
a
-
Amino
Acid
DY
erivatives anagisawa,a Yoshihiro Matsuzaki,b Hisashi Yamamoto*b
a
Department of Chemistry, Faculty of Science, Chiba University, Inage, Chiba 263-8522, Japan
b
Graduate School of Engineering, Nagoya University, CREST, Japan Science and Technology Corporation (JST), Chikusa,
Nagoya 464-8603, Japan
Fax +81(52)7893222; E-mail: yamamoto@cc.nagoya-u.ac.jp
Received 26 July 2001
lectivity (Scheme 1). We envisaged that if these chiral im-
Abstract: Chiral alcohols possessing an asymmetric 2-oxazoline
ring were synthesized as new chiral Brønsted acids from tetrahydro-
2-furoic acid and (1S, 2R)-2-amino-1,2-diphenylethanol. These al-
cohols were superior to (S,S)- or (R,R)-imide reported previously as
ides were applied to the protonation of enolates of
-
amino acid derivatives, both L- and D- -amino acids
might be selectively obtained simply by changing the
a chiral proton source for enantioselective protonation of lithium chiral proton source (Scheme 2). Thus, we initially exam-
enolate of an alanine derivative.
ined the reaction of lithium enolate 3, generated from ra-
cemic alanine derivative 2 and LDA in THF, with (R,R)-
imide 1 at –78 °C for 3 hours, however, almost no asym-
metric induction occurred in the protonation (Equation 2).
Key words: enantioselective protonation, lithium enolate -amino
acid derivative, chiral alcohols, 2-oxazoline, asymmetric catalysis
O
LiO
O
Asymmetric protonation of prochiral metal enolates has
become an efficient way of preparing nonracemic carbon-
yl compounds.1 The success of this method depends upon
the structure and acidity of the chiral proton source. Nu-
merous chiral acids have been synthesized to date and
have been utilized in enantioselective protonations.1–3
However, there are few reports on the protonation of eno-
lates of -amino acid derivatives giving rise to high asym-
metric induction.4 We describe here a new example of
enantioselective protonation of lithium enolate of an ala-
nine derivative with chiral alcohols possessing an asym-
metric 2-oxazoline ring (Equation 1).
(S,S)-imide 1
(R,R)-imide 1
R
S
THF, -78 °C
Ph
THF, -78 °C
H
H
Ph
R
Ph
Ph
87% ee
88% ee
S
S
R
H
N
H
N
N
O
N
O
O
O
O
O
(S,S)-imide 1
(R,R)-imide 1
Scheme 1
OH
O
LiO
O
(S,S)-imide 1
(R,R)-imide 1
R
Ph
R2
N
H
R
R2N
R2N
H
S
N
OR"
OR"
OR"
?
?
R'
R'
R'
O
R
Ph
D-amino acid
derivative
L-amino acid
derivative
LiO
O
Ph
Ph
Ph
Ph
chiral coordinating acids
N
N
H
OMe
OMe
*
Me
Scheme 2
Me
Equation 1
O
LiO
Ph
Ph
Ph
Ph
LDA
THF
N
H
N
OMe
OMe
We have previously shown that (S,S)-imide 1 and related
imides possessing an asymmetric 2-oxazoline are effi-
cient chiral proton sources for asymmetric protonation of
lithium enolates derived from simple ketones such as 2-
alkylcycloalkanones.5 With this imide 1, the lithium eno-
late of 2,2,6-trimethylcyclohexanone can be protonated
stereoselectively to give the original ketone in nearly 90%
ee with an (R)-configuration. Use of the enantiomer (R,R)-
imide 1 gave (S)-enriched ketone with a similar enantiose-
-78 °C, 1 h
Me
(±)-2
Me
3
O
Ph
Ph
(R,R)-imide 1
N
OMe
THF
*
Me
H
-78 °C, 3 h
2, 80% yield (<1% ee)
Equation 2
We then investigated the possibility of benzoic acid or
benzyl alcohol derivatives bearing an asymmetric 2-ox-
azoline ring as new chiral proton sources for the asymmet-
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1855,1858,ftx,en;G16301ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1856
A. Yanagisawa et al.
LETTER
ric protonation of metal enolates of amino acid corrected ee). The fact that an additional stereogenic cen-
derivatives, because these chiral Brønsted acids should ter of 18 is nearer the proton source, rather than its steric
have similar or stronger acidity compared with that of hindrance, is considered to be the key to a higher level of
(R,R)-imide 1. First, chiral benzoic acid 4 was synthesized asymmetric induction (Figure 1).
from mono-methyl phthalate (5) in four steps (Scheme 3).
The monoacid 5 was converted into the acid chloride 6 (>
99% yield) followed by reaction with (1S,2R)-2-amino-
1,2-diphenylethanol (7) leading to the amide 8 in 61%
yield. Cyclization of 8 to 2-oxazoline 9 with thionyl chlo-
ride (59% yield) and subsequent cleavage of methyl ester
by LiI/pyridine6 (54% yield) furnished (R,R)-benzoic acid
4.7 When the lithium enolate 3 was treated with a solution
of acid 4 (1.1 equiv) in THF at –78 °C for 3 hours fol-
lowed by quenching with D2O8 at –78 °C, nonracemic ala-
R
R'
Br
OH
N
N
15, R = R' = Me
Ph
Ph
16, R = R' = i-Pr
17, R = R' = c-Hex
18, R = t-Bu; R' = H
O
O
14
Ph
Ph
Figure 1
nine derivative 2 was obtained in 91% yield and 29% On the basis of the aforementioned results we designed
corrected ee9 (Equation 3).10
the new chiral alcohol 19 which has a tetrahydrofuran
(THF) ring in place of a benzene ring (Scheme 4). We
were interested in using the THF ring as a backbone of
chiral alcohol 19, because its oxygen atom was expected
to coordinate the lithium atom of the enolate 3 and form a
more rigid transition-state structure than those of chiral al-
cohols 15–18. The synthesis of chiral alcohol 19 was car-
ried out starting from racemic tetrahydro-2-furoic acid
(20). Treatment of 20 with thionyl chloride in the presence
of MeOH afforded the methyl ester 21 in 85% yield. The
ester 21 was converted to the monoester of dicarboxylic
acid 22 in 32% yield by means of carboxylation of the lith-
ium enolate generated from 21 with LDA in THF. The
monoacid was treated with (1S,2R)-2-amino-1,2-diphe-
nylethanol (7) to give amide 23 in 82% yield with an al-
most 1:1 diastereomeric ratio. These diastereomers were
separated into 23a (less polar isomer) and 23b (more polar
isomer) by column chromatography on silica gel. Both
isomers 23a and 23b were transformed into the required
chiral alcohols 19a and 19b by a three-step sequence: (1)
chlorination with thionyl chloride giving 24a (96% yield
from 23a) and 24b (85% yield from 23b), (2) cyclization
with silver triflate to form 2-oxazolines 25a and 25b in 43
and 42% yields, respectively, and (3) addition of two
equivalents of methyl Grignard furnishing the chiral alco-
hols 19a12 (from 25a) and 19b13 (from 25b).
CO2Me
CO2Me
(COCl)2, cat. DMF
CH2Cl2
0 °C ~ r.t., 4 h
CO2H
COCl
Ph
6
5
Ph
S
>99% yield
R
7
H2N
OH
Et3N, CH2Cl2, r.t., 2 h
CO2Me
CO2Me
SOCl2
H
r.t., 2 h
N
Ph
Ph
N
O
Ph
59% yield
O
9
8
HO
Ph
61% yield
LiI, pyridine
110 ~ 120 °C, 12 h
54% yield
CO2H
N
R
Ph
O
R
Ph
(R,R)-benzoic acid 4
Scheme 3
(R,R)-benzoic acid 4
LiO
O
Ph
Ph
Ph
Ph
(1.1 eq)
D2O
N
N
H
OMe
OMe
THF
-78 °C, 3 h
*
Me
Using the chiral alcohols 19a and 19b as chiral proton
sources, we attempted the asymmetric protonation of the
lithium enolate of alanine derivative 3 (Equation 4). In
these experiments we employed mesityllithium4f,h,14 in-
stead of LDA as a base for generating enolate 3 since di-
isopropylamine resulting from LDA was anticipated to
prevent alcohol 19 from coordinating the lithium of the
enolate and thus from leading to a preferable transition-
state structure. When enolate 3 was treated with a solution
of alcohol 19a in ether at –78 °C for 4 hours, (S)-enriched
alanine derivative 2 was formed in 84% yield and 53%
corrected ee (36% observed ee; 89% enolization; 67%
protonation by 19a; 22% deuteration in quench). In con-
trast, use of diastereomer 19b resulted in formation of (R)-
2 with 48% corrected ee (42% observed ee; 90% enoliza-
tion; 89% protonation by 19b; 1.4% deuteration in
quench). These results indicate that the stereochemistry at
Me
2, 91% yield
29% ee (corrected)
3
Equation 3
We further tested the ability of chiral benzyl alcohol de-
rivatives having an asymmetric 2-oxazoline moiety to
protonate the lithium enolate 3 enantioselectively. Thus,
chiral benzylic alcohols 15–18 were prepared by treating
bromo arene 14 with n-BuLi in THF at –78 °C followed
by reaction of the resulting aryl lithium with the corre-
sponding ketones or t-BuCHO. Among the chiral alcohols
examined, one diastereomer of the chiral secondary alco-
hol 1811 provided a moderate enantioselectivity (49% cor-
rected ee; 22% observed ee; 54% enolization; 44%
protonation by 18; 10% deuteration in quench), while the
chiral tertiary alcohols 15–17 were less effective (18 ~ 4%
Synlett 2001, No. 12, 1855–1858 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Protonation of Lithium Enolate of -Amino Acid Derivatives
1857
was quenched by D2O (0.3 mL) and the rate of enolization
was determined to be 89% by 1H NMR analysis (a 11% re-
duction of a peak at = 4.18 ppm was observed for the
product 2). To the other half of the mixture was added
dropwise a solution of chiral alcohol 19a (77 mg, 0.22
mmol) in ether (4 mL) at –78 °C. After being stirred for 4
hours, D2O (0.3 mL) was added to determine the percent-
age of the unreacted lithium enolate 3 (22% deuteration in
quench) and the mixture was gradually warmed to room
temperature. A saturated NH4Cl solution (10 mL) was
then added, and the organic material was extracted twice
with ether (10 mL each). The combined organic extracts
were dried over anhydrous MgSO4 and concentrated in
vacuo. The crude product was purified by column chro-
matography on silica gel to give the (S)-enriched alanine
derivative 2 (46 mg, 84% isolated yield) with 53% ee
[corrected value based on the percentage (67%) of proto-
nation by 19a and observed ee (36% ee)] which showed
the appropriate spectral data.15 The enantiomeric ratio was
determined by HPLC analysis using a chiral column
(Chiralcel OJ, Daicel Chemical Industries, Ltd., hexane/i-
PrOH = 20/1, flow rate = 0.2 mL/min): tR = 62.5 min (S-
isomer); tR = 86.2 min (R-isomer). The absolute configu-
ration was determined by comparison of its optical rota-
tion with published data.16 Alcohol 19a was recovered
(> 90% yield) without a noticeable loss of optical purity.
1) LDA/THF
0 °C, 1 h
O
O
O
CO2H
CO2Me
CO2Me
CO2H
SOCl2
MeOH
r.t., 30 min
2) CO2
20
21 (85%)
22 (32%)
Ph
Ph
S
EDCI, HOBt
Et3N, THF
r.t., 5 d
[EDCI: Me2N(CH2)3N
C NEt · HCl]
R
H2N
OH
7
CO2Me
H
CO2Me
O
O
H
SOCl2
N
Ph
Ph
N
Ph
*
*
r.t., 10 min
O
O
Cl
HO
Ph
23a (40%, less polar isomer)
23b (42%, more polar isomer)
24a (96% from 23a)
24b (85% from 23b)
AgOTf/THF
reflux, 1.5 h
Me
Me
O
O
CO2Me
N
OH
MeMgBr (4 eq)
*
*
N
R
THF
0 °C, 5 min
O
R
O
Ph
Ph
Ph
Ph
25a (43% from 24a)
25b (42% from 24b)
chiral alcohol 19:
19a (93% from 25a)
19b (39% from 25b)
Scheme 4
the new stereogenic center is more strongly influenced by
an asymmetric tetrahydrofuran ring rather than by an
asymmetric 2-oxazoline ring of the alcohols 19a and 19b.
Although further structural modifications are necessary to
obtain higher enantioselectivity, chiral alcohol 19 is a
promising chiral proton source for asymmetric protona-
tion of enolates of -amino acid derivatives.
Acknowledgement
This work was supported in part by the Ministry of Education, Sci-
ence, Sports, Culture and Technology of the Japanese Government.
References
O
LiO
Ph
Ph
Ph
Ph
mesitylLi
(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) Hünig, S. In
Houben-Weyl: Methods of Organic Chemistry, Vol. E 21;
Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,
Eds.; Georg Thieme Verlag: Stuttgart, 1995, 3851. (e)Fehr,
C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2566.
N
H
N
ether
-78 °C, 1 h
OMe
OMe
Me
Me
3
(±)-2
O
Ph
Ph
chiral alcohol 19
D2O
N
ether
-78 °C, 4 h
OMe
*
Me
H
chiral alcohol 19a: (S)-2, 84% yield
53% ee (corrected)
chiral alcohol 19b: (R)-2, >99% yield
48% ee (corrected)
(f) Yanagisawa, A.; Yamamoto, H. In Comprehensive
Asymmetric Catalysis, Vol. III; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: Berlin, 1999, 1295.
(g) Eames, J.; Weerasooriya, N. Tetrahedron: Asymmetry
2001, 12, 1.
Equation 4
(2) Recent reports using metal enolates: (a) Nishibayashi, Y.;
Takei, I.; Hidai, M. Angew. Chem. Int. Ed. 1999, 38, 3047.
(b) Yamashita, Y.; Emura, Y.; Odashima, K.; Koga, K.
Tetrahedron Lett. 2000, 41, 209. (c) Eames, J.;
A representative experimental procedure is given by the
reaction of lithium enolate 3 with chiral alcohol 19a
(Equation 4). To a solution of 2-bromomesitylene (0.067
mL, 0.44 mmol) in dry ether (2 mL) at –78 °C was added
a solution of t-BuLi (1.45 M, 0.61 mL, 0.88 mmol) in pen-
tane under an argon atmosphere. After the reaction mix-
ture had been stirred for 1 hour at –78 °C, a solution of
racemic alanine derivative 2 (110 mg, 0.40 mmol) in dry
ether (4 mL) was added at –78 °C. The reaction mixture
was held at this temperature for 1 hour, then divided into
two equal parts. A half of the resulting reaction mixture
Weerasooriya, N. Tetrahedron Lett. 2000, 41, 521.
(d) Nakamura, Y.; Takeuchi, S.; Ohgo, Y.; Curran, D. P.
Tetrahedron 2000, 56, 351. (e) Vedejs, E.; Kruger, A. W.;
Lee, N.; Sakata, S. T.; Stec, M.; Suna, E. J. Am. Chem. Soc.
2000, 122, 4602. (f) Xu, M.-H.; Wang, W.; Lin, G.-Q. Org.
Lett. 2000, 2, 2229. (g) Asensio, G.; Gaviña, P.; Cuenca, A.;
Ramírez de Arellano, C.; Domingo, L. R.; Medio-Simón, M.
Tetrahedron: Asymmetry 2000, 11, 3481. (h) Wang, W.;
Xu, M.-H.; Lei, X.-S.; Lin, G.-Q. Org. Lett. 2000, 2, 3773.
(i) Xu, M.-H.; Wang, W.; Xia, L.-J.; Lin, G.-Q. J. Org.
Chem. 2001, 66, 3953.
Synlett 2001, No. 12, 1855–1858 ISSN 0936-5214 © Thieme Stuttgart · New York

1858
A. Yanagisawa et al.
LETTER
(3) Recent reports using silyl enol ethers, ketene silyl acetals or
other enolic species: (a) Hénin, F.; Létinois, S.; Muzart, J.
Tetrahedron: Asymmetry 2000, 11, 2037. (b) Nakamura, S.;
Kaneeda, M.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc.
2000, 122, 8120. (c) Matsukawa, S.; Imamoto, T. J. Am.
Chem. Soc. 2000, 122, 12659. (d) Roy, O.; Diekmann, M.;
Riahi, A.; Hénin, F.; Muzart, J. Chem. Commun. 2001, 533.
(4) For enantioselective protonations of metal enolates of -
amino acid derivatives, see: (a) Duhamel, L.; Plaquevent, J.-
C. J. Am. Chem. Soc. 1978, 100, 7415. (b) Duhamel, L.;
Plaquevent, J.-C. Tetrahedron Lett. 1980, 21, 2521.
(c) Duhamel, L.; Plaquevent, J.-C. Bull. Soc. Chim. Fr. 1982,
II, 75. (d) Duhamel, L.; Fouquay, S.; Plaquevent, J.-C.
Tetrahedron Lett. 1986, 27, 4975. (e) Duhamel, L.;
Duhamel, P.; Fouquay, S.; Eddine, J. J.; Peschard, O.;
Plaquevent, J.-C.; Ravard, A.; Solliard, R.; Valnot, J.-Y.;
Vincens, H. Tetrahedron 1988, 44, 5495. (f) Vedejs, E.;
Lee, N. J. Am. Chem. Soc. 1995, 117, 891. (g) Martin, J.;
Lasne, M.-C.; Plaquevent, J.-C.; Duhamel, L. Tetrahedron
Lett. 1997, 38, 7181. (h) Vedejs, E.; Kruger, A. W.; Suna, E.
J. Org. Chem. 1999, 64, 7863. (i) Calmès, M.; Glot, C.;
Martinez, J. Tetrahedron: Asymmetry 2001, 12, 49.
(5) (a) Yanagisawa, A.; Kuribayashi, T.; Kikuchi, T.;
Yamamoto, H. Angew. Chem., Int. Ed. Engl. 1994, 33, 107.
(b) Yanagisawa, A.; Kikuchi, T.; Watanabe, T.;
R1
R1
R1
CO2H
N
CO2H
R2
R3
Ph
Ph
N
O
R1
O
R4
R5
10, R1 = Cl; R2 = R4 = H; R3 = R5 = Ph
13
11, R1 = H; R2 = R4 = 2-MeC6H4; R3 = R5 = H
12, R1 = H; R2 = R4 = 3,5-tBu2C6H3; R3 = R5 = H
Figure 2
(11) Spectral data of one diastereomer of 18 (less polar isomer):
TLC Rf = 0.14 (1:2 ether/hexane); IR (CHCl3): 3900–3150,
3013, 2975, 1690, 1509, 1472, 1397, 1225 cm–1; 1H NMR
(300 MHz, CDCl3): = 0.86 (s, 9 H, 3 CH3), 4.00 (s, 1 H,
OH), 4.95–4.97 (m, 3 H, 3 CH), 7.13–7.49 (m, 13 H,
aromatic), 7.93 (m, 1 H, aromatic); 13C NMR (75 MHz,
CDCl3): = 25.2 (3 C), 35.9, 67.6, 78.4, 91.0, 122.7, 123.4,
126.7 (2 C), 127.1, 127.8 (4 C), 127.9 (3 C), 128.5, 131.0,
131.6, 142.0, 142.1, 144.7, 161.4; [ ]30D –85.4 (c 1.0,
CHCl3).
(12) Spectral data of 19a: TLC Rf = 0.43(ether); IR (CHCl3):
3700–3200, 3019, 2982, 1653, 1497, 1456, 1374, 1215
cm–1; 1H NMR (300 MHz, CDCl3): = 1.38 (s, 3 H, CH3),
1.42 (s, 3 H, CH3), 2.05 (m, 2 H, CH2), 2.41 (m, 2 H, CH2),
3.71 (s, 1 H, OH), 4.04 (dd, 1 H, J = 6.9, 13.5 Hz, one proton
of CH2), 4.14 (dd, 1 H, J = 7.2, 14.4 Hz, one proton of CH2),
5.10 (d, 1 H, J = 7.8 Hz, CH), 5.26 (d, 1 H, J = 8.1 Hz, CH),
7.20–7.40 (m, 10 H, aromatic); 13C NMR (75 MHz, CDCl3):
= 25.2, 25.3, 26.2, 32.2, 70.1, 73.6, 78.2, 88.2, 89.2, 125.8
(2 C), 126.5 (2 C), 127.8, 128.5, 128.8 (2 C), 128.9 (2 C),
139.9, 141.6, 170.1; [ ]30D +40.2 (c 1.0, CHCl3).
(13) Spectral data of 19b: TLC Rf = 0.53(ether); IR (CHCl3):
3650–3200, 3017, 2982, 1649, 1495, 1456, 1374, 1215
cm–1; 1H NMR (300 MHz, CDCl3): = 1.37 (s, 3 H, CH3),
1.46 (s, 3 H, CH3), 2.05 (m, 2 H, CH2), 2.40 (m, 2 H, CH2),
3.81 (s, 1 H, OH), 4.09 (m, 2 H, CH2), 5.13 (d, 1 H, J = 8.7
Hz, CH), 5.28 (d, 1 H, J = 8.4 Hz, CH), 7.21–7.41 (m, 10 H,
aromatic); 13C NMR (75 MHz, CDCl3): = 25.0, 25.3, 26.2,
32.2, 70.1, 73.5, 78.4, 88.1, 89.2, 126.0 (2 C), 126.5 (2 C),
127.8, 128.6, 128.8 (2 C), 129.0 (2 C), 139.9, 141.5, 170.1;
[ ]30D +108.9 (c 1.0, CHCl3).
Kuribayashi, T.; Yamamoto, H. Synlett 1995, 372.
(c) Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett
1997, 411. (d) Yanagisawa, A.; Kikuchi, T.; Yamamoto, H.
Synlett 1998, 174. (e) Yanagisawa, A.; Kikuchi, T.;
Kuribayashi, T.; Yamamoto, H. Tetrahedron 1998, 54,
10253. (f) Yanagisawa, A.; Watanabe, T.; Kikuchi, T.;
Yamamoto, H. J. Org. Chem. 2000, 65, 2979.
(6) (a) McMurry, J. E. Org. React. 1976, 24, 187. (b) Magnus,
P.; Gallagher, T. J. Chem. Soc., Chem. Commun. 1984, 389.
(7) Spectral data of 4: TLC Rf = 0.05 (1:2 ethyl acetate/hexane);
IR (KBr): 3200–2250, 3040, 1709, 1653, 1495, 1456, 1283
cm–1; 1H NMR (300 MHz, CDCl3): = 5.46 (d, 1 H, J = 8.1
Hz, CH), 5.58 (d, 1 H, J = 8.4 Hz, CH), 7.24–7.68 (m, 10 H,
aromatic), 7.67 (dt, 1 H, J = 1.5, 7.5 Hz, aromatic), 7.76 (dt,
1 H, J = 1.5, 7.5 Hz, aromatic), 8.24 (dd, 1 H, J = 1.5, 7.5 Hz,
aromatic), 8.67 (dt, 1 H, J = 1.2, 7.5 Hz, aromatic); 13C NMR
(75 MHz, CDCl3): = 76.3, 77.7, 89.9, 123.4, 126.0 (2 C),
126.3 (2 C), 128.6, 129.2 (2 C), 129.3 (2 C), 129.4, 131.0,
132.0, 133.1, 135.6, 137.9, 139.1, 166.8 (2 C); [ ]23D +70.7
(c 1.0, CHCl3).
(8) D2O was added as a quencher to determine a percentage of
the unreacted enolate 3. As for an experimental procedure
for the D2O quench, see the representative experimental
procedure in the text.
(9) Corrected value based on the percentage of the protonated
product. The details of the protonation are as follows: 13%
observed ee; 54% enolization; 44% protonation by 4; 10%
deuteration in quench.
(14) Beck, A. K.; Hoekstra, M. S.; Seebach, D. Tetrahedron Lett.
1977, 1187.
(15) Spectral data of 2:16 TLC Rf = 0.30 (1:2 ether/hexane);
IR(neat): 2990, 2950, 1742, 1624, 1599, 1578, 1491, 1447,
1287, 1206 cm–1; 1H NMR (300 MHz, CDCl3): = 1.42 (d,
3 H, J = 6.9 Hz, CH3), 3.72 (s, 3 H, CH3), 4.18 (q, 1 H,
J = 6.9 Hz, CH), 7.17–7.21 (m, 2 H, aromatic), 7.30–7.49
(m, 6 H, aromatic), 7.62–7.66 (m, 2 H, aromatic); 13C NMR
(75 MHz, CDCl3): = 19.2, 52.1, 60.6, 127.6 (2 C), 128.0 (2
C), 128.6 (3 C), 128.7 (2 C), 130.3, 136.2, 139.4, 169.7,
173.4. Observed [ ]D value of (R)-2 (42% ee) obtained in the
protonation with 19b: [ ]28D +24.8 (c 1.0, CHCl3).
(16) Polt, R.; Peterson, M. A.; DeYoung, L. J. Org. Chem. 1992,
57, 5469.
(10) We studied the enantioselectivity of the protonation of other
chiral benzoic acids 10–13 derived from various amino
alcohols and diacids, however, no results better than those
with acid 4 were obtained (Figure 2).
Synlett 2001, No. 12, 1855–1858 ISSN 0936-5214 © Thieme Stuttgart · New York