Asymmetric synthesis of α,α-disubstituted α-amino acids using (S,S)-cyclohexane-1,2-diol as a chiral auxiliary

Article abstract of DOI:10.1021/jo001423m

Diastereoselective alkylation of ethyl 2-methyl- and/or 2-ethylacetoacetates using the (S,S)-cyclohexane-1,2-diol as an acetal chiral auxiliary afforded enol ethers (2a-f and 5a-f) of 92->95% de in 31-70% yields. Removal of the cyclohexane-1,2-diol with BF₃-OEt₂ afforded β-keto esters (3 and 6) bearing a chiral quaternary carbon. The β-keto esters could be easily converted into optically active α-methylated and/or α-ethylated α,α-disubstituted amino acids (12 and 13) in 21-99% yields using Schmidt rearrangement.

Full text of DOI:10.1021/jo001423m

J . Org. Chem. 2001, 66, 2667-2673
2667
Asym m etr ic Syn th esis of r,r-Disu bstitu ted r-Am in o Acid s Usin g
(S,S)-Cycloh exa n e-1,2-d iol a s a Ch ir a l Au xilia r y
Masakazu Tanaka,* Makoto Oba, Koichi Tamai, and Hiroshi Suemune*
Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, J apan
mtanaka@phar.kyushu-u.ac.jp
Received September 29, 2000
Diastereoselective alkylation of ethyl 2-methyl- and/or 2-ethylacetoacetates using the (S,S)-
cyclohexane-1,2-diol as an acetal chiral auxiliary afforded enol ethers (2a -f and 5a -f) of 92->95%
de in 31-70% yields. Removal of the cyclohexane-1,2-diol with BF3-OEt2 afforded â-keto esters (3
and 6) bearing a chiral quaternary carbon. The â-keto esters could be easily converted into optically
active R-methylated and/or R-ethylated R,R-disubstituted amino acids (12 and 13) in 21-99% yields
using Schmidt rearrangement.
In tr od u ction
and cyclic R,R-disubstituted amino acids7 because these
achiral R,R-disubstituted amino acids could be easily
prepared. Recently, peptides containing the chiral R,R-
disubstituted amino acids were prepared, and their
conformational studies revealed the relationship between
the chirality of R,R-disubstituted amino acids and the
sense of helicity in the peptides.8 However, the difficulty
in asymmetric synthesis of the chiral R,R-disubstituted
amino acids, which bear a chiral quaternary carbon,
restricts the available chiral R,R-disubstituted amino
acids for the conformational study of peptides containing
such residues.1
Here, we wish to report practical and facile syntheses
of various chiral R,R-disubstituted amino acids, such as
R-methylleucine (RMeLeu), R-ethylleucine (REtLeu), and
R-ethylvaline (REtVal), using the (S,S)-cyclohexane-1,2-
diol as a chiral auxiliary.9
R,R-Disubstituted R-amino acids are nonproteinogenic
modified amino acids, in which the hydrogen atom at the
R-position of natural R-amino acids is replaced with an
alkyl substituent.1 The R-alkyl substituents in R,R-
disubstituted amino acids severely restrict the confor-
mational freedom of peptides containing such residues,
and these amino acids are used as a probe to investigate
the biologically active conformation,2 to study the second-
ary structure of peptides,3 and to search the origin of
chirality.4 The conformational studies of R,R-disubstitut-
ed amino acids have concentrated on achiral amino acids,
such as R-aminoisobutyric acid (Aib),3a,5 diethylglycine,6
* To whom correspondence should be addressed. Tel: + 81-92-
642-6604. Fax:
phar.kyushu-u.ac.jp)
+
81-92-642-6545. (H.S. e-mail: suemune@
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Ed. Engl. 1996, 35, 2708. (b) Wirth, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 225. (c) Cativiela, C.; D.-de-Villegas, M. D. Tetrahedron:
Asymmetry 1998, 9, 3517. (d) Cativiela, C.; D.-de-Villegas, M. D.
Tetrahedron: Asymmetry 2000, 11, 645. (e) M.-Manas, M.; Trepat, E.;
Sebastian, R. M.; Vallribera, A. Tetrahedron: Asymmetry 1999, 10,
4211. (f) Berkowitz, D. B.; McFadden, J . M.; Sloss, M. K. J . Org. Chem.
2000, 65, 2907.
Resu lts a n d Discu ssion
Syn th etic Str a tegy. We have previously reported the
asymmetric alkylation of cyclic â-keto esters using the
(S,S)-cycloalkane-1,2-diols as chiral acetal auxiliaries.9,10
(2) (a) Obrecht, D.; Abrecht, C.; Altorfer, M.; Bohdal, U.; Grieder,
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Tetrahedron 1999, 55, 585.
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Chem. Soc. 1997, 119, 12048.(c) Wolf, W. M.; Stasiak, M.; Leplawy,
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Soc. 1998, 120, 11558. (d) Koch, K. N.; Linden, A.; Heimgartner, H.
Helv. Chim. Acta 2000, 83, 233.
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A.; Crisma, M.; Valle, G.; Toniolo, C. Biopolymers 1989, 28, 175. (b)
Gatos, M.; Formaggio, F.; Crisma, M.; Toniolo, C.; Bonora, G. M.;
Benedetti, Z.; Blasio, B. D.; Iacovino, R.; Santini, A.; Saviano, M.;
Kamphuis, J . J . Pept. Res. 1997, 3, 110. (c) Wolf, W. M.; Stasiak, M.;
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G.; Precigoux, G.; Aubry, A.; Kamphuis, J . Biopolymers 1993, 33, 1061.
(b) Polese, A.; Formaggio, F.; Crisma, M.; Valle, G.; Toniolo, C.; Bonora,
G. M.; Broxterman, Q. B.; Kamphuis, J . Chem. Eur. J . 1996, 2, 1104.
(c) J aun, B.; Tanaka, M.; Seiler, P.; Ku¨hnle, F. N. M.; Braun, C.;
Seebach, D. Liebigs Ann./ Recueil 1997, 1697. (d) Lim, D.; Burgess, K.
J . Am. Chem. Soc. 1997, 119, 9632. (e) Gratias, R.; Konat, R.; Kessler,
H.; Crisma, M.; Valle, G.; Polese, A.; Formaggio, F.; Toniolo, C.;
Broxterman, Q. B.; Kamphuis, J . J . Am. Chem. Soc. 1998, 120, 4763.
(f) Imawaka, N.; Tanaka, M.; Suemune, H. Helv. Chim. Acta 2000,
83, 2823. (g) Tanaka, M.; Oba, M.; Imawaka, N.; Tanaka, Y.; Kurihara,
M.; Suemune, H. Helv. Chim. Acta 2001, 84, 32.
(9) (a) Sakai, K.; Suemune, H. Tetrahedron Asymmetry 1993, 4,
2109. (b) Suemune, H.; Yoshida, O.; Uchida, J .; Nomura, Y.; Tanaka,
M.; Sakai, K. Tetrahedron Lett. 1995, 36, 7259. (c) Yamada, S.;
Karasawa, S.; Takahashi, Y.; Aso, M.; Suemune, H. Tetrahedron 1998,
54, 15555.
(10) (a) Kato, K.; Sakai, K.; Suemune, H. Tetrahedron Lett. 1992,
33, 247. (b) Kato, K.; Sakai, K.; Suemune, H. Tetrahedron 1994, 50,
3315.
(4) Cronin, J . R.; Pizzarello, S. Sciences 1997, 275, 951.
(5) (a) Blasio, D. B.; Pavone, V.; Saviano, M.; Lombardi, A.; Nastri,
F.; Pedone, C.; Benedetti, E.; Crisma, M.; Anzoline, M.; Toniolo, C. J .
Am. Chem. Soc. 1992, 114, 6273. (b) Karle, I. L.; Rao, R. B.; Prasad,
S.; Kaul, R.; Balaram, P. J . Am. Chem. Soc. 1994, 116, 10356.
(6) (a) Benedetti, E.; Barone, V.; Bavoso, A.; Blasio, B. D.; Lelj, F.;
Pavone, V.; Pedone, C.; Bonora, G. M.; Toniolo, C.; Leplawy, M. T.;
Kaczmarek, K.; Redlinski, A. Biopolymers 1988, 27, 357. (b) Toniolo,
C.; Bonora, G. M.; Bavoso, A.; Benedetti, E.; Blasio, B. D.; Pavone, V.;
Pedone, C.; Barone, V.; Lelj, F.; Leplawy, M. T.; Kaczmarek, K.;
Redlinski, A. Biopolymers 1988, 27, 373. (c) Tanaka, M.; Imawaka,
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10.1021/jo001423m CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/28/2001

2668 J . Org. Chem., Vol. 66, No. 8, 2001
Tanaka et al.
Sch em e 1
F igu r e 1. Synthetic strategy for chiral R,R-disubstituted
amino acids.
These methods could be applied to acyclic â-keto esters,
and therefore the chiral quaternary carbons would be
efficiently constructed. It was thought that the Beckmann
or Schmidt rearrangement from â-keto esters bearing a
quaternary carbon would afford the chiral R,R-disubsti-
tuted R-amino acids. The methyl and ethyl groups were
selected as the R1-substituents because the conformations
of R-methylated and R-ethylated R,R-disubstituted amino
acids are very different,8f and practical methods for
synthesis of such chiral R,R-disubstituted amino acids are
desired among peptide and medicinal chemists (Figure
1).
Asym m etr ic Alk yla tion of Acyclic â-Keto Ester s.
Ethyl 2-methylacetoacetate and ethyl 2-ethylacetoacetate
were converted into chiral acetals 1 and 4 in 81% and
56% yields, respectively, by treatment with (S,S)-cyclo-
hexane-1,2-diol and p-toluenesulfonic acid in refluxing
benzene. The acetals 1 and 4 were diastereomeric mix-
tures with regard to the R-methyl and R-ethyl substitu-
ents. The 1H NMR spectrum of 1 showed the methine
proton signals of the C(2)-position at δ 2.82 (q, J ) 7.0
Hz) and 2.74 (q, J ) 7.0 Hz) in the ratio of 1 to 1, and
that of 4 showed the methine signals at δ 2.63 (dd, J )
4.0, 11.2 Hz) and 2.54 (dd, J ) 3.6, 10.6) in the ratio of
1 to 1. The separation of diastereomers was difficult by
column chromatography, but the diastereomeric mixtures
could be used for asymmetric alkylation without problem.
The acetal 1 was alkylated into enol ethers 2a -f by
treatment with LDA (5 equiv), alkyl halide (5 equiv), and
HMPA (5 equiv) in THF (Scheme 1 ) (Table 1). The
alkylated products were obtained in moderate chemical
yields (56-64%), except for 2d and 2e. The yields of 2d
(32%) and 2e (42%) were somewhat low because alkyl
iodides such as i-Pr-I and i-Bu-I are less reactive than
primary alkyl halides. In these cases (entry 4 and 5),
unalkylated product 7, R,â-unsaturated enol ether, was
isolated as a major byproduct.
Ta ble 1. Dia ster eoselective Alk yla tion of Aceta ls
1 a n d 4a
enol ether
â-keto ester
entry
R-X
yield (%) de (%)b
yield (%)
[R]D
1
2
3
4
5
6
7
8
9
Bn-Br
n-Pr-I 2b
n-Bu-I
i-Pr-I
i-Bu-I
allyl-Br 2f
Bn-Br 5a
n-Pr-I 5b
n-Bu-I
i-Pr-I
i-Bu-I
2a
57
63
94
>95
>95
93
95
>95
92
>95
>95
>95
>95
>95
3a
3b
3c
3d
3e
3f
6a
6b
6c
6d
6e
6f
73
79
78
75
85
82
84
76
79
85
85
78
-58.5c
-9.0
2c
2d
2e
56
-6.4
32d
42d
64
+26.8
-3.1
-28.1c
-34.7
+3.2
69
70
5c
5d
5e
58
+6.6
10
11
12
31d
45d
66
-19.2
-9.3
allyl-Br 5f
-14.1
a
The reactions were carried out at - 78 °C f - 40 °C using
LDA (5 equiv), alkyl halide (5 equiv), and HMPA (5 equiv) in THF.
Diastereomer excesses were determined by 1H NMR spectra of
b
â-keto esters using (+)-Eu(hfc)3. c Literature12 R ) Bn, [R]D
)
d
- 58.2 (92% ee); R ) allyl, [R]D ) - 27.9 (94% ee). The reaction
was carried out at - 78 °C f room temp.
The diastereomer excesses of 2a -f could not be deter-
1
mined at this stage by using H NMR spectra or HPLC
esters (()-3, but the signals derived from the enantio-
merically enriched 3 appeared in a different ratio or as
only one peak. Furthermore, the â-keto ester 3e was
converted into (R,R)-(-)-2,3-butanediol acetal 9, and the
analysis; therefore, the enol ethers 2 were converted into
â-keto esters 3 by treatment with BF3-OEt2, and the
diastereomer excess of 2 was determined as an enantio-
meric excess of 3. The enantiomeric excesses of 3a -f were
determined by 1H NMR spectra using a chiral shift
reagent (+)-Eu(hfc)3.11 In the case that the chemical shift
of the methyl proton signal in the acetyl function of 3
was shifted from δ 2 into δ 4 using the shift reagent, the
methyl signal equally split away in the racemic â-keto
1
measurement of H NMR spectra confirmed the enan-
tiomeric excesses. The enantiomeric excess determined
by this method was identical with that measured by the
shift reagent methodology. The diastereomer excesses of
all products were high (93->95% de). The absolute
configuration of products 3a and 3f were determined by
comparison of the specific rotations with those of reported
values. That is to say, the specific rotation of 3a was
(11) Eu(hfc)3: Tris[3-(heptafluoropropylhydroxymethylene)-(+)-cam-
phorato], europium(III) derivative.

Asymmetric Synthesis of R,R-Disubstituted R-Amino Acids
J . Org. Chem., Vol. 66, No. 8, 2001 2669
Sch em e 2
F igu r e 2. Plausible mechanism of diastereoselection.
-58.5, and the reported value of (S)-3a was -58.2 (92%
ee).12 Therefore, the absolute stereochemistry of 3a was
unambiguously determined to be S; also that of 3f was
determined to be S.12 The absolute configuration of the
other products was determined to be S, based on the
assumption that the same course of stereocontrol oc-
curred in these reactions.
Ta ble 2. Sch m id t Rea r r a n gem en t of â-Keto Ester s
3 a n d 6
R,R-disubstituted amino acid
entry
â-keto ester
yield (%)
[R]D
1
2
3
4
5
6
7
8
9
3a
Bn
12a
12b
12c
12d
12e
12f
13a
13b
13c
13d
13e
13f
95
99
89
50
80
44
52
48a
37a
21a
35a
-
-63.8b
-12.6
-14.6
+2.8
-29.1
-16.4
-107.1
-15.6
-16.4
-10.5
-21.2
3b
3c
3d
3e
3f
6a
6b
6c
6d
6e
6f
n-Pr
n-Bu
i-Pr
i-Bu
allyl
Bn
n-Pr
n-Bu
i-Pr
i-Bu
allyl
The acetal 4 was also alkylated into enol ethers 5-f
under the same reaction conditions. The alkylated prod-
ucts 5 were obtained in moderate chemical yields (58-
70%), except for 5d and 5e. In the case of 5d and 5e, the
unalkylated product 8, which was an R,â-unsaturated
enol ether, was isolated as a byproduct. The diastereomer
excesses of 5a -f were determined after conversion into
10
11
12
1
â-keto esters 6 by the H NMR spectra in the presence
of (+)-Eu(hfc)3. The diastereomer excesses of 5 (92->95%
de) were high enough to use the â-keto esters for the
preparation of R,R-disubstituted amino acids. The abso-
lute configuration of (+)-6c was determined to be (S)-6c
(vide infra) after converting to R,R-disubstituted amino
acid. In the case that the (R,R)-cyclohexane-1,2-diol was
used as a chiral auxiliary, the alkylation of â-keto ester
afforded an enantiomer. For example, the alkylation of
4 bearing an (S,S)-cyclohexane-1,2-diol with i-Bu-I af-
forded (+)-5e, and that of 4 bearing an (R,R)-diol afforded
(-)-5e.
The diastereoselection of the alkylation reaction could
be explained by the assumption of a chelated intermedi-
ate, as shown in Figure 2.10 In the plausible intermediate,
one lithium cation chelated to two oxygens of the chiral
auxiliary and to the oxygen of ethyl ester. On the basis
of this model, the re-face of the C(2)-position might be
shielded by the (S,S)-cyclohexane-1,2-diol moiety, and the
electrophiles could exclusively attack the si-face of the
enolate to afford (2S)-products 3 and 6.
Syn th esis of r,r-Disu bstitu ted Am in o Acid s. The
conversion of â-keto esters 3 and 6 to the R,R-disubsti-
tuted amino acids was first attempted using the Beck-
mann rearrangement reaction reported by Frutos et al.13
However, in the case of R-ethylated â-keto ester, the yield
of the Beckmann rearrangement was very poor. For
example, the conversion of oxime 11 into 13a was only
13% yield. Furthermore, even in the case of R-methylated
â-keto ester 3a , the reproducibility in the Beckmann
rearrangement of 10 was not good (Scheme 2).
Next, we examined use of the Schmidt rearrangement
reported by Georg et al.12b The â-keto esters 3 and 6 were
treated with NaN3 and methanesulfonic acid in refluxing
CHCl3 to afford the R,R-disubstituted amino acids 12 and
13. The results are summarized in Table 2. The Schmidt
a
The â-keto esters 6 were recovered as starting materials. See
Experimental Section. Literature12 [R]D ) -47.8°.
b
rearrangement of the R-methylated â-keto esters 3
required 5-6 h, and the R-methylated R,R-disubstituted
amino acids 12 were obtained in good yields (44-99%).
The reaction of the R-ethylated â-keto esters 6 required
long reaction time (20-24 h), and the yields of the
R-ethylated R,R-disubstituted amino acids 13 were mod-
erate (21-52%). In some cases, the â-keto esters 6 were
recovered in 45-58% yields. Taking the recovery of the
substrates into account, the conversion yields of 13b-e
were 27-83%.
The absolute configuration of products 12 was assumed
to be R14 because the Schmidt rearrangement proceeded
with retention of stereochemistry at the R-carbon of the
carbonyl function. Moreover, the absolute configuration
of R-methylated amino acid 12a was determined to be R
by comparison of the specific rotation with the reported
value.12b The absolute configuration of R-ethylated amino
acid 13c was determined to be R by comparison of the
specific rotation with the material (S)-butylethylglycine,
which was prepared by another route.15,16 The absolute
configuration of R-ethylated leucine (+)-13e prepared
using (R,R)-cyclohexane-1,2-diol was unambiguously de-
termined to be S by X-ray crystallographic analysis of
its dipeptide with (S)-butylethylglycine.15,17 J udging from
these results, we would say that the absolute stereo-
chemistry of the R,R-disubstituted amino acids 12 and
13 prepared using (S,S)-cyclohexane-1,2-diol is R. The
enantiomeric excess of 13e was confirmed to be >95%
1
ee by the H NMR spectra in the presence of the chiral
(14) Conversion of â-keto esters into R,R-disubstituted amino acids
changes the priority of ligands at the quaternary carbon in the Cahn-
Ingold-Prelog system. The stereochemistry of the quaternary carbon
was retained.
(12) (a) Tomioka, K.; Ando, K.; Takemasa, Y.; Koga, K. J . Am. Chem.
Soc. 1984, 106, 2718. (b) Georg, G. I.; Guan, X.; Kant, J . Tetrahedron
Lett. 1988, 29, 403.
(15) Liu, W.; Ray, P.; Benezra, S. A. J . Chem. Soc., Perkin Trans. 1
1995, 553.
(16) Acetylation of (S)-(+)-butylethylglycine ethyl ester [(S)-Beg-
(13) Frutos, R. P.; Spero, D. M. Tetrahedron Lett. 1998, 39, 2475.
OEt]14 afforded (+)-13c; [R]23 +16.8 (c 1.68, CHCl3).
D

2670 J . Org. Chem., Vol. 66, No. 8, 2001
Tanaka et al.
m/z 256 (M+, 80), 214 (27), 188 (42), 126 (38), 61 (100); HRMS
calcd for C14H24O4 (M+) 256.1674, found 256.1671.
1
shift reagent (+)-Eu(hfc)3. The H NMR spectrum of (()-
13e showed the methyl proton signals of ethyl ester at δ
2.43 (t, J ) 7.1 Hz) and 2.41 (t, J ) 7.1 Hz) in the ratio
of 1 to 1, while the corresponding signal from (-)-13e
and (+)-13e showed only one peak (t, J ) 7.1 Hz) in the
presence of (+)-Eu(hfc)3, respectively. This result means
that no epimerization occurred in the Schmidt rearrange-
ment.
Eth yl (2S)-2-Ben zyl-2-m eth yl-3-[(1S,2S)-2-h yd r oxycy-
cloh exyloxy]-3-bu ten oa te (2a ). n-BuLi (1.4 mL, 2.25 mmol,
1.5 M in hexane) was added dropwise to the stirred solution
of diisopropylamine (223 mg, 2.25 mmol) in THF (8 mL) at
-78 °C, the solution was warmed to 0 °C, and then stirred for
30 min at 0 °C. The solution was cooled to -78 °C, HMPA
(403 mg, 2.25 mmol) was added, and then 1 (120 mg, 0.45
mmol) in THF (2 mL) was added dropwisely. The solution was
stirred at -78 °C for 30 min, and then benzyl bromide (450
mg, 2.25 mmol) was added dropwise to the stirred solution.
The solution was stirred at -78 °C for 3 h, -40 °C for 2 h,
and diluted with saturated aqueous NH4Cl. The whole was
extracted with EtOAc and dried over MgSO4. Removal of the
solvent afforded an oily residue, which was purified by column
chromatography on silica gel. The fraction eluted with 10%
EtOAc in hexane gave enol ether 2a (84 mg, 51%) as a colorless
Con clu sion
A practical procedure for the synthesis of various chiral
R,R-disubstituted amino acids has been developed using
the cyclohexane-1,2-diol as a chiral auxiliary. Both the
optically pure (S,S)- and (R,R)-cyclohexane-1,2-diols,9a
which are easily prepared by the kinetic resolution of
racemic diacetate using lipase, can be available on the
scale of grams; therefore, these methods would provide
both enantiomers of various R,R-disubstituted amino
acids. The preparation of peptides containing R,R-disub-
stituted amino acids described here, and their conforma-
tional analysis are currently under way.6c,d,17,18
oil: [R]22 +58.8 (c 1.50, CHCl3); IR (neat) 3500 (br), 1730,
D
1660, 1620 cm-1; 1H NMR (CDCl3) δ 7.10-7.26 (m, 5H), 4.15-
4.27 (m, 2H), 4.14 (d, J ) 3.0 Hz, 1H), 3.90 (d, J ) 3.0 Hz,
1H), 3.84 (m, 1H), 3.59 (m, 1H), 3.29 (s, 1H), 3.27 (d, J ) 14.0
Hz, 1H), 3.00 (d, J ) 14.0 Hz, 1H), 2.04-2.24 (m, 2H), 1.73-
1.82 (m, 2H), 1.20-1.41 (m, 4H), 1.28 (t, J ) 7.0 Hz, 3H), 1.21
(s, 3H); FAB(+) HRMS calcd for C20H29O4 (M+ + H) 333.2066,
found 333.2065.
Eth yl (2S)-2-Meth yl-2-p r op yl-3-[(1S,2S)-2-h yd r oxycy-
cloh exyloxy]-3-bu ten oa te (2b). Compound 2b was prepared
from 1 in a manner similar to that described for the prepara-
Exp er im en ta l Section
1H NMR spectra were determined at 270 MHz unless
otherwise noted. Benzene was distilled from P2O5. THF was
purchased from Kanto Chemical Co. and used without distil-
lation. Infrared spectra were recorded on a J ASCO A-100
spectrometer (KBr or neat). EIMS, FABMS, and HRMS
spectra were taken on a J EOL J MS 610H or J EOL SX102
spectrometer. Elemental analyses were performed in the
Analytical Center of the Graduate School of Science at Kyushu
University. The other general procedures were followed as
described in the previous papers.10
tion of 2a : 63%; a colorless oil; [R]23 +50.8 (c 1.30, CHCl3);
D
IR (neat) 3480 (br), 1720, 1640, 1610 cm-1; H NMR (CDCl3)
1
δ 4.08-4.21 (m, 2H), 4.16 (d, J ) 3.0 Hz, 1H), 4.12 (d, J ) 3.0
Hz, 1H), 3.78 (m, 1H), 3.51 (m, 1H), 3.12 (br s, 1H), 2.01-2.11
(m, 2H), 1.60-1.88 (m, 4H), 1.14-1.41 (m, 4H), 1.31 (s, 3H),
1.27 (t, J ) 7.0 Hz, 3H), 0.93 (t, J ) 7.0 Hz, 3H); FAB(+)
HRMS calcd for C16H29O4 (M+ + H) 285.2066, found 285.2060.
Eth yl (2S)-2-Bu tyl-2-m eth yl-3-[(1S,2S)-2-h yd r oxycyclo-
h exyloxy]-3-bu ten oa te (2c). Compound 2c was prepared
from 1 in a manner similar to that described for the prepara-
Eth yl (2RS)-3,3-[(1S,2S)-Cycloh exa n e-1,2-d ioxy]-2-m e-
th ylbu ta n oa te (1).10 A mixture of ethyl 2-methylacetoacate
(450 mg, 3.1 mmol), (S,S)-cyclohexane-1,2-diol (242 mg, 2.1
mmol), and p-toluenesulfonic acid monohydrate (38 mg, 0.2
mmol) in benzene (30 mL) was refluxed for 10 h, fixed with
Dean-Stark apparatus. After being cooled to room tempera-
ture, the mixture was diluted with EtOAc, washed with 5%
aqueous NaHCO3, brine, and dried over MgSO4. After removal
of the solvent, the residue was purified by column chroma-
tography on silica gel (10% EtOAc in hexane) to give 1 (407
mg, 81% based on cyclohexanediol) as a colorless oil: IR (neat)
tion of 2a : 56%; a colorless oil; [R]23 +49.3 (c 1.30, CHCl3);
D
IR (neat) 3500 (br), 1730, 1650, 1610 cm-1; H NMR (CDCl3)
1
δ 4.16 (d, J ) 2.3 Hz, 1H), 4.12 (d, J ) 2.3 Hz, 1H), 4.08-4.21
(m, 2H), 3.78 (m, 1H), 3.54 (m, 1H), 3.12 (br s, 1H), 2.01-2.11
(m, 2H), 1.61-1.90 (m, 4H), 1.09-1.41 (m, 8H), 1.30 (s, 3H),
1.27 (t, J ) 7.0 Hz, 3H), 0.91 (t, J ) 7.0 Hz, 3H); FAB(+)
HRMS calcd for C17H31O4 (M+ + H) 299.2222, found 299.2225.
Eth yl (2S)-2-Isop r op yl-2-m eth yl-3-[(1S,2S)-2-h yd r oxy-
cycloh exyloxy]-3-bu ten oa te (2d ). Compound 2d was pre-
pared from 1 in a manner similar to that described for the
1730 cm-1; H NMR (CDCl3) δ 4.19-4.21 (m, 2H), 3.36-3.22
1
preparation of 2a : 32%; a colorless oil; [R]20 +95.1 (c 1.00,
D
CHCl3); IR (neat) 3500 (br), 1720, 1650, 1615 cm-1; H NMR
1
(m, 2H), 2.82 (q, J ) 7.0 Hz, 0.5H), 2.74 (q, J ) 7.0 Hz, 0.5H),
2.10-2.15 (m, 2H), 1.78-1.85 (m, 2H), 1.47 (s, 1.5H), 1.48 (s,
1.5H), 1.21-1.44 (m, 10H); EIMS m/z 243 (M+ + 1, 28), 229
(34), 180 (25), 157 (45), 98 (100).
(CDCl3) δ 4.10-4.18 (m, 4H), 3.70 (m, 1H), 3.55 (m, 1H), 3.54
(br s, 1H), 2.62 (septet, J ) 7.0 Hz, 1H), 2.02-2.17 (m, 2H),
1.70-1.76 (m, 2H), 1.16-1.36 (m, 4H), 1.27 (t, J ) 7.0 Hz, 3H),
1.21 (s, 3H), 0.87 (d, J ) 7.0 Hz, 6H); FAB(+) HRMS calcd for
Eth yl (2RS)-3,3-[(1S,2S)-Cycloh exa n e-1,2-d ioxy]-2-eth -
ylbu ta n oa te (4). Compound 4 was prepared from ethyl
2-ethylacetoacate in a manner similar to that described for
C
16H29O4 (M+ + H) 285.2066, found 285.2061.
E t h yl (2S)-2-Isobu t yl-2-m et h yl-3-[(1S,2S)-2-h yd r oxy-
the preparation of 1: 56%; a colorless oil; IR (neat) 1735 cm-1
;
cycloh exyloxy]-3-bu ten oa te (2e). Compound 2e was pre-
pared from 1 in a manner similar to that described for the
1H NMR (CDCl3) δ 4.13-4.24 (m, 2H), 3.20-3.39 (m, 2H), 2.63
(dd, J ) 4.0, 11.2 Hz, 0.5H), 2.54 (dd, J ) 3.6, 10.6 Hz, 0.5H),
2.09-2.17 (m, 2H), 1.63-1.98 (m, 4H), 1.47 (s, 1.5H), 1.46 (s,
1.5H), 1.30 (t, J ) 7.0 Hz, 3H), 0.93 (t, J ) 7.6 Hz, 3H); EIMS
preparation of 2a : 42%; a colorless oil; [R]26 +61.5 (c 0.70,
D
CHCl3); IR (neat) 3500 (br), 1720, 1645, 1610 cm-1; H NMR
1
(CDCl3) δ 4.07-4.21 (m, 4H), 3.77 (m, 1H), 3.52 (m, 1H), 3.32
(br s, 1H), 2.02-2.12 (m, 2H), 1.83 (m, 1H), 1.59-1.73 (m, 4H),
1.16-1.36 (m, 4H), 1.35 (s, 3H), 1.25 (t, J ) 7.0 Hz, 3H), 0.90
(d, J ) 6.4 Hz, 3H), 0.89 (d, J ) 6.5 Hz, 3H); FAB(+) HRMS
calcd for C17H31O4 (M+ + H) 299.2222, found 299.2220.
Eth yl (2S)-2-Allyl-2-m eth yl-3-[(1S,2S)-2-h yd r oxycyclo-
h exyloxy]-3-bu ten oa te (2f). Compound 2f was prepared
from 1 in a manner similar to that described for the prepara-
(17) Dipeptide CF3CO-REtLeu-(S)-Beg-OEt was prepared by using
solution phase methods, and the X-ray analysis revealed that the
configuration of (+)-13e prepared using (R,R)-cyclohexane-1,2-diol was
S. Crystal data of CF3CO-REtLeu-(S)-Beg-OEt: solvent of recryst. )
MeOH, C20H35O4N2F3, Mr ) 424.50, orthorhombic, space group P212121
(No. 19), a ) 11.301, b ) 11.318, c ) 19.284 Å, V ) 2466.5 Å3, Z ) 4,
Dcalcd ) 1.143 gcm-3, µ (Mo-KR) ) 0.093 cm-1, no. of observation ) 1829
(I > 2.0 σ(Ι)), R ) 0.075, Rw ) 0.103. The synthesis and conformational
analysis of peptides will be published elsewhere.
(18) While we were preparing the manuscript, Maruoka et al.
reported the enantioselective synthesis of R-allylated and R-methylated
R-amino acids using chiral phase-transfer catalyst. See: Ooi, T.;
Takeuchi, M.; Kameda, M.; Maruoka, K. J . Am. Chem. Soc. 2000, 122,
5228.
tion of 2a : 64%; a colorless oil; [R]22 +68.8 (c 1.10, CHCl3);
D
IR (neat) 3500 (br), 1730, 1650, 1620 cm-1; H NMR (CDCl3)
1
δ 5.68 (m, 1H), 5.03-5.09 (m, 2H), 4.09-4.21 (m, 2H), 4.17 (d,
J ) 3.3 Hz, 1H), 4.10 (d, J ) 3.3 Hz, 1H), 3.78 (m, 1H), 3.53
(m, 1H), 3.07 (br s, 1H), 2.65 (dd, J ) 6.1, 13.6 Hz, 1H), 2.42
(dd, J ) 8.3, 13.6 Hz, 1H), 2.01-2.11 (m, 2H), 1.69-1.72 (m,

Asymmetric Synthesis of R,R-Disubstituted R-Amino Acids
J . Org. Chem., Vol. 66, No. 8, 2001 2671
2H), 1.29 (s, 3H), 1.25 (t, J ) 7.3 Hz, 3H), 1.15-1.45 (m, 4H);
FAB(+) HRMS calcd for C16H27O4 (M+ + H) 283.1909, found
283.1913.
dried over MgSO4. Removal of the solvent afforded an oily
residue, which was purified by column chromatography on
silica gel (3% EtOAc in hexane) to give â-keto ester 3a (68
Eth yl (2S)-2-Ben zyl-2-eth yl-3-[(1S,2S)-2-h yd r oxycyclo-
h exyloxy]-3-bu ten oa te (5a ). Compound 5a was prepared
from 4 in a manner similar to that described for the prepara-
mg, 73%) as a colorless oil: [R]27 -58.5 (c 1.30, CHCl3), lit.12
D
[R]D -58.2 (92% ee); IR (neat) 1740, 1710 cm-1
;
1H NMR
(CDCl3) δ 7.03-7.28 (m,5H), 4.14-4.25 (m, 2H), 3.29 (d, J )
14.0 Hz, 1H), 3.04 (d, J ) 14.0 Hz, 1H), 2.17 (s, 3H), 1.28 (s,
3H), 1.25 (t, J ) 7.2 Hz, 3H); FAB(+) HRMS calcd for C14H19O3
(M+ + H) 235.1334, found 235.1331.
tion of 2a : 69%; a colorless oil; [R]23 +45.7 (c 1.40, CHCl3);
D
IR (neat) 3500 (br), 1725, 1650, 1620 cm-1; H NMR (CDCl3)
1
δ 7.08-7.34 (m, 5H), 4.02-4.35 (m, 2H), 4.25 (d, J ) 3.3 Hz,
1H), 3.88 (d, J ) 3.3 Hz, 1H), 3.82 (m, 1H), 3.58 (m, 1H), 3.20
(d, J ) 13.5 Hz, 1H), 3.09 (d, J ) 13.5 Hz, 1H), 2.70 (br, 1H),
2.22 (m, 1H), 2.03 (m, 1H), 1.53-1.81 (m, 4H), 1.20-1.45 (m,
4H), 1.31 (t, J ) 7.0 Hz, 3H), 0.95 (t, J ) 7.0 Hz, 3H); FAB(+)
HRMS calcd for C21H31O4 (M+ + H) 347.2222, found 347.2226.
Eth yl (2S)-2-Eth yl-2-p r op yl-3-[(1S,2S)-2-h yd r oxycyclo-
h exyloxy]-3-bu ten oa te (5b). Compound 5b was prepared
from 4 in a manner similar to that described for the prepara-
Eth yl (S)-2-Meth yl-2-p r op yla cetoa ceta te (3b). Com-
pound 3b was prepared from 2b in a manner similar to that
described for the preparation of 3a : 79%; a colorless oil; [R]24
D
-9.1 (c 1.30, CHCl3); IR (neat) 1720, 1700 cm-1
;
1H NMR
(CDCl3) δ 4.23 (q, J ) 7.3 Hz, 2H), 2.16 (s, 3H), 1.67-1.92 (m,
2H), 1.32 (s, 3H), 1.28 (t, J ) 7.0 Hz, 3H), 1.12-1.30 (m, 2H),
0.95 (t, J ) 6.9 Hz, 3H); FAB(+) HRMS calcd for C10H19O3
(M+ + H) 187.1334, found 187.1330.
tion of 2a : 70%; a colorless oil; [R]20 +60.5 (c 1.00, CHCl3);
Eth yl (S)-2-Bu tyl-2-m eth yla cetoa ceta te (3c). Compound
3c was prepared from 2c in a manner similar to that described
D
IR (neat) 3500 (br), 1720, 1650, 1620 cm-1; H NMR (CDCl3)
1
δ 4.05-4.23 (m, 2H), 4.19 (d, J ) 3.3 Hz, 1H), 4.12 (d, J ) 3.3
Hz, 1H), 3.77 (m, 1H), 3.51 (m, 1H), 2.75 (br s, 1H), 2.00-2.22
(m, 2H), 1.62-1.88 (m, 6H), 1.00-1.40 (m, 6H), 1.27 (t, J )
7.0 Hz, 3H), 0.92 (t, J ) 7.0 Hz, 3H), 0.83 (t, J ) 7.0 Hz, 3H);
FAB(+) HRMS calcd for C17H31O4 (M+ + H) 299.2222, found
299.2224.
for the preparation of 3a : 78%; a colorless oil; [R]24 -5.4 (c
D
1.24, CHCl3); IR (neat) 1720 (br) cm-1; 1H NMR (CDCl3) δ 4.23
(q, J ) 7.3 Hz, 2H), 2.14 (s, 3H), 1.67-1.94 (m, 2H), 1.32 (s,
3H), 1.28 (t, J ) 7.3 Hz, 3H), 1.10-1.37 (m, 4H), 0.92 (t, J )
7.0 Hz, 3H); FAB(+) HRMS calcd for C11H21O3 (M+ + H)
201.1491, found 201.1495.
Eth yl (2S)-2-Bu tyl-2-eth yl-3-[(1S,2S)-2-h yd r oxycyclo-
h exyloxy]-3-bu ten oa te (5c). Compound 5c was prepared
from 4 in a manner similar to that described for the prepara-
Eth yl (S)-2-Isop r op yl-2-m eth yla cetoa ceta te (3d ). Com-
pound 3d was prepared from 2d in a manner similar to that
described for the preparation of 3a : 78%; a colorless oil; [R]18
D
tion of 2a : 58%; a colorless oil; [R]30 +34.0 (c 0.50, CHCl3);
+26.8 (c 1.00, CHCl3); IR (neat) 1735, 1715 cm-1
;
1H NMR
D
IR (neat) 3450 (br), 1730, 1650, 1620 cm-1; H NMR (CDCl3)
(CDCl3) δ 4.22 (q, J ) 7.2 Hz, 2H), 2.64 (septet, J ) 6.9 Hz,
1H), 2.16 (s, 3H), 1.28 (t, J ) 7.2 Hz, 3H), 1.24 (s, 3H), 0.93 (d,
J ) 6.9 Hz, 3H), 0.84 (d, J ) 6.9 Hz, 3H); FAB(+) HRMS calcd
for C10H19O3 (M+ + H) 187.1334, found 187.1331.
1
δ 4.02-4.25 (m, 2H), 4.22 (d, J ) 3.3 Hz, 1H), 4.14 (d, J ) 3.3
Hz, 1H), 3.78 (m, 1H), 3.54 (m, 1H), 2.72 (br s, 1H), 1.98-2.15
(m, 2H), 1.64-1.89 (m, 6H), 1.00-1.40 (m, 8H), 1.28 (t, J )
7.6 Hz, 3H), 0.96 (t, J ) 7.0 Hz, 3H), 0.83 (t, J ) 7.6 Hz, 3H);
FAB(+) HRMS calcd for C18H33O4 (M+ + H) 313.2379, found
313.2384.
Eth yl (S)-2-Isobu tyl-2-m eth yla cetoa ceta te (3e). Com-
pound 3e was prepared from 2e in a manner similar to that
described for the preparation of 3a : 85%; a colorless oil; [R]31
D
Eth yl (2S)-2-Eth yl-2-isop r op yl-3-[(1S,2S)-2-h yd r oxycy-
cloh exyloxy]-3-bu ten oa te (5d ). Compound 5d was prepared
from 4 in a manner similar to that described for the prepara-
-3.1 (c 1.50, CHCl3); IR (neat) 1730, 1705 cm-1
;
1H NMR
(CDCl3) δ 4.22 (q, J ) 7.3 Hz, 2H), 2.15 (s, 3H), 1.93 (dd, J )
14.2, 6.9 Hz, 1H), 1.77 (dd, J ) 14.2, 5.6 Hz, 1H), 1.64 (m,
1H), 1.35 (s, 3H), 1.26 (t, J ) 7.3 Hz, 3H), 0.89 (d, J ) 6.6 Hz,
6H); FAB(+) HRMS calcd for C11H21O3 (M+ + H) 201.1491,
found 201.1494.
tion of 2a : 31%; a colorless oil; [R]28 +43.1 (c 1.10, CHCl3);
D
IR (neat) 3500 (br), 1715, 1640, 1610 cm-1; H NMR (CDCl3)
1
δ 4.10-4.28 (m, 3H), 4.03 (d, J ) 3.3 Hz, 1H), 3.76 (m, 1H),
3.53 (br s, 1H), 3.51 (m, 1H), 2.02-2.25 (m, 2H), 1.66-1.93
(m, 5H), 1.22-1.37 (m, 4H), 1.28 (t, J ) 7.0 Hz, 3H), 0.97 (d,
J ) 7.0 Hz, 3H), 0.88 (d, J ) 7.0 Hz, 3H), 0.84 (t, J ) 7.0 Hz,
3H); FAB(+) HRMS calcd for C17H31O4 (M+ + H) 299.2222,
found 299.2225.
Eth yl (S)-2-Allyl-2-m eth yla cetoa ceta te (3f). Compound
3f was prepared from 2f in a manner similar to that described
for the preparation of 3a : 82%; a colorless oil; [R]19 -28.1 (c
D
0.80, CHCl3); IR (neat) 1730, 1700 cm-1; H NMR (CDCl3) δ
1
5.65 (m, 1H), 5.06-5.13 (m, 2H), 4.23 (q, J ) 7.2 Hz, 2H), 2.68
(dd, J ) 7.0, 14.2 Hz, 1H), 2.54 (dd, J ) 7.6, 14.2 Hz, 1H),
2.15 (s, 3H), 1.33 (s, 3H), 1.29 (t, J ) 7.2 Hz, 3H); FAB(+)
HRMS calcd for C10H17O3 (M+ + H) 185.1178, found 185.1181.
Eth yl (S)-2-Ben zyl-2-eth yla cetoa ceta te (6a ). Compound
6a was prepared from 5a in a manner similar to that described
Eth yl (2S)-2-Eth yl-2-isobu tyl-3-[(1S,2S)-2-h yd r oxycy-
cloh exyloxy]-3-bu ten oa te (5e). Compound 5e was prepared
from 4 in a manner similar to that described for the prepara-
tion of 2a : 45%; a colorless oil; [R]26 +49.3 (c 0.90, CHCl3);
D
IR (neat) 3500 (br), 1730, 1645, 1610 cm-1; H NMR (CDCl3)
1
δ 4.03-4.24 (m, 4H), 3.77 (m, 1H), 3.50 (m, 1H), 2.87 (br s,
1H), 2.00-2.23 (m, 2H), 1.55-1.90 (m, 7H), 1.13-1.36 (m, 4H),
1.24 (t, J ) 7.0 Hz, 3H), 0.90 (d, J ) 6.4 Hz, 3H), 0.87 (d, J )
6.4 Hz, 3H), 0.81 (t, J ) 7.4 Hz, 3H); FAB(+) HRMS calcd for
for the preparation of 3a : 84%; a colorless oil; [R]20 -34.7 (c
D
1.10, CHCl3); IR (neat) 1740, 1710 cm-1; H NMR (CDCl3) δ
1
5.50-5.66 (m, 5H), 4.10-4.23 (m, 2H), 3.24 (d, J ) 14.1 Hz,
1H), 3.14 (d, J ) 14.1 Hz, 1H), 2.10 (s, 3H), 1.90 (q, J ) 7.6
Hz, 2H), 1.26 (t, J ) 7.0 Hz, 3H), 0.90 (t, J ) 7.6 Hz, 3H);
FAB(+) HRMS calcd for C15H21O3 (M+ + H) 249.1491, found
249.1495.
C
18H33O4 (M+ + H) 313.2379, found 313.2381. The alkylation
using (R,R)-cyclohexane-1,2-diol gave (2R)-(-)-5e; [R]28D -47.7
(c 0.98, CHCl3).
E t h yl (2S)-2-Allyl-2-et h yl-3-[(1S,2S)-2-h yd r oxycyclo-
h exyloxy]-3-bu ten oa te (5f). Compound 5f was prepared
from 4 in a manner similar to that described for the prepara-
Eth yl (S)-2-Eth yl-2-p r op yla cetoa ceta te (6b). Compound
6b was prepared from 5b in a manner similar to that described
for the preparation of 3a : 76%; a colorless oil; [R]25 +3.20 (c
D
tion of 2a : 66%; a colorless oil; [R]19 +65.0 (c 0.70, CHCl3);
0.30, CHCl3); IR (neat) 1740, 1710 cm-1; H NMR (CDCl3) δ
1
D
IR (neat) 3500 (br), 1730, 1645, 1615 cm-1; H NMR (CDCl3)
4.23 (q, J ) 7.3 Hz, 2H), 2.11 (s, 3H), 1.71-1.98 (m, 4H), 1.28
(t, J ) 7.3 Hz, 3H), 1.03-1.16 (m, 2H), 0.95 (t, J ) 7.0 Hz,
3H), 0.79 (t, J ) 7.6 Hz, 3H); FAB(+) HRMS calcd for C11H21O3
(M+ + H) 201.1491, found 201.1489.
1
δ 5.65 (m, 1H), 5.02-5.11 (m, 2H), 4.10-4.24 (m, 4H), 3.79
(m, 1H), 3.55 (m, 1H), 2.72 (br s, 1H), 2.61 (dd, J ) 6.6, 13.9
Hz, 1H), 2.50 (dd, J ) 8.1, 13.9 Hz, 1H), 2.01-2.13 (m, 2H),
1.68-1.85 (m, 4H), 1.18-1.37 (m, 4H), 1.29 (t, J ) 7.3 Hz, 3H),
0.84 (t, J ) 7.3 Hz, 3H); FAB(+) HRMS calcd for C17H29O4
(M+ + H) 297.2066, found 297.2068.
Eth yl (S)-2-Ben zyl-2-m eth yla cetoa ceta te (3a ). BF3-
OEt2 (1 mL, 8 mmol) was added dropwise to the stirred
solution of 2a (132 mg, 0.40 mmol) in EtOH (8 mL) and H2O
(1 mL) at room temperature. After being stirred for 3 h, the
solution was diluted with brine, extracted with EtOAc, and
Eth yl (S)-2-Bu tyl-2-eth yla cetoa ceta te (6c). Compound
6c was prepared from 5c in a manner similar to that described
for the preparation of 3a : 79%; a colorless oil; [R]26 +6.60 (c
D
1.10, CHCl3); IR (neat) 1735, 1710 cm-1; H NMR (CDCl3) δ
1
4.23 (q, J ) 7.3 Hz, 2H), 2.11 (s, 3H), 1.79-1.98 (m, 4H), 1.23-
1.36 (m, 2H), 1.28 (t, J ) 7.3 Hz, 3H), 1.01-1.11 (m, 2H), 0.92
(t, J ) 7.2 Hz, 3H), 0.79 (t, J ) 7.3 Hz, 3H); FAB(+) HRMS
calcd for C12H23O3 (M+ + H) 215.1647, found 215.1645.

2672 J . Org. Chem., Vol. 66, No. 8, 2001
Tanaka et al.
Eth yl (S)-2-Eth yl-2-isop r op yla cetoa ceta te (6d ). Com-
pound 6d was prepared from 5d in a manner similar to that
(5 mL) was stirred at 60 °C for 10 h. The mixture was diluted
with brine, extracted with EtOAc, and dried over MgSO4.
Removal of the solvent afforded an oily residue, which was
purified by column chromatography on silica gel. The fraction
eluted with 2% EtOAc in hexane gave 11 (197 mg, 80%) as a
described for the preparation of 3a : 85%; a colorless oil; [R]26
D
-19.2 (c 1.20, CHCl3); IR (neat) 1740, 1710 cm-1
;
1H NMR
(CDCl3) δ 4.26 (q, J ) 7.3 Hz, 2H), 2.43 (septet, J ) 6.9 Hz,
1H), 2.16 (s, 3H), 1.82-2.03 (m, 2H), 1.31 (t, J ) 7.3 Hz, 3H),
0.93 (d, J ) 6.9 Hz, 6H), 0.81 (t, J ) 7.6 Hz, 3H); FAB(+)
HRMS calcd for C11H21O3 (M+ + H) 201.1491, found 201.1493.
E t h yl (S)-2-E t h yl-2-isob u t yla cet oa cet a t e (6e). Com-
pound 6e was prepared from (+)-5e in a manner similar to
that described for the preparation of 3a : 85%; a colorless oil;
colorless oil: [R]22D -42.4 (c 2.00, CHCl3); IR (neat) 1735 cm-1
;
1H NMR (CDCl3) δ 7.82 (d, J ) 8.6 Hz, 2H), 7.30 (d, J ) 8.6
Hz, 2H), 7.10-7.20 (m, 3H), 6.90-6.95 (m, 2H), 4.00-4.20 (m,
2H), 3.16 (d, J ) 14.2 Hz, 1H), 3.02 (d, J ) 14.2 Hz, 1H), 2.44
(s, 3H), 1.61-1.87 (m, 2H), 1.82 (s, 3H), 1.17 (t, J ) 7.0 Hz,
3H), 0.75 (t, J ) 7.6 Hz, 3H); FAB(+) HRMS calcd for
[R]31 -9.30 (c 1.50, CHCl3); IR (neat) 1740, 1710 cm-1
;
1H
C
22H28N1O5S1 (M+ + H) 418.1688, found 418.1691.
D
NMR (CDCl3) δ 4.22 (q, J ) 7.0 Hz, 2H), 2.12 (s, 3H), 1.92-
2.50 (m, 2H), 1.78-1.90 (m, 2H), 1.55 (m, 1H), 1.26 (t, J ) 7.0
Hz, 3H), 0.87 (d, J ) 6.6 Hz, 3H), 0.85 (d, J ) 6.6 Hz, 3H),
0.75 (d, J ) 7.6 Hz, 3H); FAB(+) HRMS calcd for C12H23O3
(M+ + H) 215.1647, found 215.1645. The specific rotation of
(R)-N-Acet yl-r-m et h ylp h en yla la n in e E t h yl E st er
(12a ).12b Methansulfonic acid (0.73 mL, 10.0 mmol) was added
dropwise to the stirred solution of â-keto ester 3a (234 mg,
1.00 mmol) in CHCl3 (5 mL) at 0 °C, and then NaN3 (325 mg,
5.0 mmol) was added. After being refluxing for 6 h, the reaction
mixture was cooled to room temperature, diluted with H2O,
neutralized with diluted aqueous NH3, extracted with ether,
and dried over MgSO4. Removal of the solvent afforded an oily
residue, which was purified by column chromatography on
silica gel (10% EtOAc in hexane) to give 12a (237 mg, 95%) as
6e prepared using (R,R)-cyclohexane-1,2-diol showed [R]26
D
+9.17 (c 1.15, CHCl3).
Eth yl (S)-2-Allyl-2-eth yla cetoa ceta te (6f). Compound 6f
was prepared from 5f in a manner similar to that described
for the preparation of 3a : 78%; a colorless oil; [R]19 -14.1 (c
D
0.90, CHCl3); IR (neat) 1740, 1720 cm-1; H NMR (CDCl3) δ
1
a colorless oil: [R]28 -63.8 (c 1.10, CHCl3), lit.12b [R]D -47.8
D
(>95% ee); IR (neat) 3300 (br), 1720, 1660 cm-1
;
1H NMR
5.58 (m, 1H), 5.04-5.13 (m, 2H), 4.23 (q, J ) 7.1 Hz, 2H), 2.53-
2.65 (m, 2H), 2.13 (s, 3H), 1.99 (m, 2H), 1.29 (t, J ) 7.1 Hz,
3H), 0.81 (t, J ) 7.6 Hz, 3H); FAB(+) HRMS calcd for C11H19O3
(M+ + H) 199.1334, found 199.1331.
(CDCl3) δ 7.18-7.30 (m, 3H), 7.02-7.08 (m, 2H), 6.09 (br s,
1H), 4.29 (m, 2H), 3.60 (d, J ) 13.5 Hz, 1H), 3.21 (d, J ) 13.5
Hz, 1H), 1.96 (s, 3H), 1.66 (s, 3H), 1.35 (t, J ) 7.0 Hz, 3H); 13
C
E t h yl 3-[(1S,2S)-2-Hyd r oxycycloh exyloxy]-2-m et h yl-
bu t-2-en oa te (7): a colorless oil; IR (neat) 3410 (br), 1700,
NMR (CDCl3) δ 173.9, 169.5, 136.6, 129.8, 128.2, 126.8, 61.8,
61.2, 41.0, 24.0, 23.4, 14.1; FABMS m/z 250 (M+ + H).
1610 cm-1 1H NMR (CDCl3) δ 4.12-4.28 (m, 2H), 3.60 (m,
;
(R)-N-Acetyl-r-m eth ylp r op ylglycin e Eth yl Ester (12b).
Compound 12b was prepared from 3b in a manner similar to
that described for the preparation of 12a : 99%; colorless
1H), 2.80 (m, 1H), 2.17 (br s, 3H), 1.92 (br s, 3H), 1.11-2.20
(m, 12H); FAB(+) HRMS calcd for
243.1596, found 243.1592.
C
13H23O4 (M+ + H)
crystals; mp 74-75 °C; [R]23 -12.6 (c 1.10, CHCl3); IR (KBr)
D
Eth yl 2-Eth yl-3-[(1S,2S)-2-h yd r oxycycloh exyloxy]bu t-
2-en oa te (8): a colorless oil; IR (neat) 3420 (br), 1695, 1610
3300 (br), 1740, 1660 cm-1; 1H NMR (CDCl3) δ 6.29 (br s, 1H),
4.22 (q, J ) 7.3 Hz, 2H), 2.28 (ddd, J ) 1.6, 11.9, 13.5 Hz,
1H), 1.97 (s, 3H), 1.73 (ddd, J ) 4.6, 11.9, 13.5 Hz, 1H), 1.56
(s, 3H), 1.27 (t, J ) 7.3 Hz, 3H), 0.95-1.22 (m, 2H), 0.89 (t, J
) 7.3 Hz, 3H); 13C NMR (CDCl3) δ 174.3, 169.0, 61.2, 60.0,
38.6, 23.5, 22.7, 17.2, 13.9, 13.8; FABMS m/z 202 (M+ + H).
Anal. Calcd for C10H19N1O3: C, 59.68; H, 9.52; N, 6.96.
Found: C, 59.53; H, 9.44; N, 7.30.
1
cm-1; H NMR (CDCl3) δ 5.30 (br s, 1H), 4.10-4.30 (m, 2H),
3.52-3.68 (m, 2H), 1.90-2.35 (m, 4H), 1.98 (s, 3H), 1.65-1.80
(m. 2H), 1.29 (t, J ) 7.3 Hz, 3H), 1.20-1.50 (m, 4H), 1.00 (t,
J ) 7.4 Hz, 3H),; FAB(+) HRMS calcd for C14H25O4 (M+ + H)
257.1753, found 257.1758.
(R,R)-2,3-Bu ta n ed iol Aceta l of 3e (9). A mixture of â-keto
ester 3e (30 mg, 1.15 mmol), (R,R)-(-)-2,3-butanediol (18 mg,
0.2 mmol), and p-toluenesulfonic acid monohydrate (3 mg) in
benzene (10 mL) was refluxed for 3 h, fixed with Dean-Stark
apparatus. After being cooled to room temperature, the
mixture was diluted with ether, washed with 5% aqueous
NaHCO3, brine, and dried over MgSO4. After removal of the
solvent, the residue was briefly purified by column chroma-
tography on silica gel to afford 9 as a colorless oil. The 500
MHz 1H NMR spectrum of acetal 9 derived from the â-keto
ester (()-3e showed the methyl proton signals at δ 1.37 (s,
1.5H) and 1.35 (s, 1.5H) in the ratio of 1 to 1, while the
corresponding signal from (-)-3e alkylated by our methods
was observed at δ 1.35 (s, 3H), only.
Eth yl (2S)-2-Ben zyl-2-m eth yl-3-(N-p-tolu en esu lfon yl-
oxyim in o)bu ta n oa te (10).13 1H NMR (CDCl3) δ 7.82 (d, J )
8.6 Hz, 2H), 7.28 (d, J ) 8.6 Hz, 2H), 7.13-7.35 (m, 3H), 6.90-
6.95 (m, 2H), 4.15 (q, J ) 7.0 Hz, 2H), 3.19 (d, J ) 13.5 Hz,
1H), 3.02 (d, J ) 13.5 Hz, 1H), 2.44 (s, 3H), 1.90 (s, 3H), 1.23
(s, 3H)., 1.18 (t, J ) 7.0 Hz, 3H).
(R)-N-Acetyl-r-bu tylm eth ylglycin e Eth yl Ester (12c).
Compound 12c was prepared from 3c in a manner similar to
that described for the preparation of 12a : 89%; colorless
crystals; mp 70-71 °C (recryst. from hexane); [R]23 -14.6 (c
D
1
1.10, CHCl3); IR (KBr) 3300 (br), 1735, 1650 cm-1; H NMR
(CDCl3) δ 6.40 (br s, 1H), 4.21 (q, J ) 7.3 Hz, 2H), 2.26 (m,
1H), 1.99 (s, 3H0, 1.79 (m, 1H), 1.58 (s, 3H), 0.93-1.36 (m,
4H), 1.28 (t, J ) 7.3 Hz, 3H), 0.87 (t, J ) 7.1 Hz, 3H); 13C
NMR (CDCl3) δ 174.6, 169.0, 61.4, 60.3, 36.0, 26.3, 23.8, 22.9,
22.5, 14.0, 13.8; FABMS m/z 216 (M+ + H). Anal. Calcd for
11H21N1O3: C, 61.37; H, 9.83; N, 6.51. Found: C, 61.32; H,
9.83; N, 6.54.
(R)-N-Acetyl-r-m eth ylva lin e Eth yl Ester (12d ). Com-
pound 12d was prepared from 3d in a manner similar to that
C
described for the preparation of 12a : 50%; a colorless oil; [R]24
D
+2.80 (c 0.58, CHCl3); IR (neat) 3300 (br), 1735, 1660 cm-1
;
1H NMR (CDCl3) δ 6.03 (br s, 1H), 4.20 (q, J ) 6.9 Hz, 2H),
2.27 (septet, J ) 6.9 Hz, 1H), 1.98 (s, 3H), 1.57 (s, 3H), 1.28 (t,
J ) 6.9 Hz, 3H), 0.98 (d, J ) 6.9 Hz, 3H), 0.89 (d, J ) 6.9 Hz,
3H); FAB(+) HRMS calcd for C10H20N1O3 (M+ + H) 202.1443,
found 202.1445.
Eth yl (2S)-2-Ben zyl-2-eth yl-3-(N-p-tolu en esu lfon ylim i-
n o)bu ta n oa te (11). A mixture of 6a (315 mg, 1.27 mmol),
NaOAc (26 mg, 0.32 mmol), and NH2OH-HCl (176 mg, 2.54
mmol) in EtOH (6 mL) was stirred at 50 °C for 8 h. The
mixture was diluted with saturated aqueous NH4Cl, extracted
with CHCl3, and dried over Na2SO4. After removal of the
solvent, the residue was purified by column chromatography
on silica gel (3% EtOAc in hexane) to afford oxime (216 mg,
65%): colorless crystals; [R]20D -20.8 (c 0.50, CHCl3); IR (KBr)
(R)-N-Acetyl-r-m eth ylleu cin e Eth yl Ester (12e). Com-
pound 12e was prepared from 3e in a manner similar to that
described for the preparation of 12a : 80%; colorless crystals;
mp 54-55 °C (recryst. from hexane); [R]27 -29.1 (c 1.10,
D
CHCl3); IR (KBr) 3300 (br), 1730, 1650 cm-1; 1H NMR (CDCl3)
δ 6.56 (br s, 1H), 4.22 (q, J ) 7.3 Hz, 2H), 2.37 (dd, J ) 5.0,
13.9 Hz, 1H), 1.99 (s, 3H), 1.52-1.72 (m, 2H), 1.59 (s, 3H),
1.30 (t, J ) 7.3 Hz, 3H), 0.90 (d, J ) 6.6 Hz, 3H), 0.81 (d, J )
6.6 Hz, 3H); 13C NMR (CDCl3) δ 175.3, 168.9, 61.5, 59.9, 44.2,
24.6, 24.0, 23.9, 23.6, 22.8, 13.9; FABMS m/z 216 (M+ + H).
Anal. Calcd for C11H21N1O3: C, 61.37; H, 9.83; N, 6.51.
Found: C, 61.25; H, 9.77; N, 6.56.
1
3450 (br), 3300 (br), 1720 cm-1; H NMR (CDCl3) δ 8.32 (br,
1H), 7.03-7.27 (m, 5H), 4.08-4.22 (m, 2H), 3.25 (d, J ) 13.9
Hz, 1H), 3.13 (d, J ) 13.9 Hz, 1H), 1.79 (s, 3H), 1.64-1.82 (m,
2H), 1.27 (t, J ) 7.3 Hz, 3H), 0.91 (t, J ) 7.6 Hz, 3H); FABMS
m/z 263 (M+ + H). A mixture of oxime (155 mg, 0.59 mmol),
4-DMAP (7 mg), and p-TsCl (228 mg, 1.20 mmol) in pyridine

Asymmetric Synthesis of R,R-Disubstituted R-Amino Acids
J . Org. Chem., Vol. 66, No. 8, 2001 2673
(R)-N-Acetyl-r-a llylm eth ylglycin e Eth yl Ester (12f).
Compound 12f was prepared from 3f in a manner similar to
that described for the preparation of 12a : 44%; a colorless oil;
(m, 3H), 1.30 (t, J ) 7.2 Hz, 3H), 0.88 (m, 1H), 0.86 (t, J ) 7.0
Hz, 3H), 0.73 (t, J ) 7.0 Hz, 3H); FAB(+) HRMS calcd for
C12H24N1O3 (M+ + H) 230.1756, found 230.1756.
[R]23 -16.4 (c 1.09, CHCl3); IR (neat) 3300 (br), 1730, 1660
(R)-N-Acetyl-r-eth ylva lin e Eth yl Ester (13d ). Com-
pound 13d was prepared from 6d in a manner similar to that
described for the preparation of 12a : 13d : 21%. Coumpound
D
1
cm-1; H NMR (CDCl3) δ 6.23 (br s, 1H), 5.65 (m, 1H), 5.13
(br s, 1H), 5.08 (m, 1H), 4.21 (q, J ) 7.3 Hz, 2H), 2.99 (dd, J
) 7.3, 13.9 Hz, 1H), 2.55 (dd, J ) 7.6, 13.9 Hz, 1H), 1.98 (s,
3H), 1.59 (s, 3H), 1.28 (t, J ) 7.3 Hz, 3H); FAB(+) HRMS calcd
for C10H18N1O3 (M+ + H) 200.1287, found 200.1290.
6d was recovered in 21%. 13d : a colorless oil; [R]24 -10.5 (c
D
0.71, CHCl3); IR (neat) 3400, 3300 (br), 1715, 1655 cm-1; H
1
NMR (CDCl3) δ 6.47 (br s, 1H), 4.25 (q, J ) 6.9 Hz, 2H), 2.63
(septet, J ) 6.9 Hz, 2H), 2.02 (s, 3H), 1.97 (septet, J ) 7.3 Hz,
1H), 1.31 (t, J ) 6.9 Hz, 3H), 0.98 (d, J ) 6.9 Hz, 3H), 0.88 (d,
J ) 6.9 Hz, 3H), 0.73 (t, J ) 7.3 Hz, 3H); FAB(+) HRMS calcd
for C11H22N1O3 (M+ + H) 216.1600, found 216.1603.
(R)-N-Acetyl-r-eth ylp h en yla la n in e Eth yl Ester (13a ).
Compound 13a was prepared from 6a in a manner similar to
that described for the preparation of 12a : 52%; a colorless oil;
[R]30 -107.2 (c 1.40, CHCl3); IR (neat) 3400 (br), 3300 (br),
D
1725, 1645 cm-1; 1H NMR (CDCl3) δ 7.18-7.30 (m, 3H), 7.02-
7.08 (m, 2H), 6.17 (br s, 1H), 4.17-4.34 (m, 2H), 3.79 (d, J )
13.5 Hz, 1H), 3.11 (d, J ) 13.5 Hz, 1H), 2.71 (m, 1H), 1.98 (s,
3H), 1.93 (m, 1H), 1.37 (t, J ) 7.0 Hz, 3H), 0.81 (t, J ) 7.0 Hz,
3H); FAB(+) HRMS calcd for C14H20N1O3 (M+ + H) 250.1443,
found 250.1448.
(R)-N-Acetyl-r-eth ylleu cin e Eth yl Ester (13e). Com-
pound 13e was prepared from 6e in a manner similar to that
described for the preparation of 12a . 13e: 35%. Compound
6e was recovered in 40%. 13e: colorless crystals; mp 42-43
°C (recryst. from hexane); [R]27D -21.2 (c 1.00, CHCl3); IR (KBr)
3400 (br), 3300 (br), 1720, 1645 cm-1; 1H NMR (CDCl3) δ 6.53
(br s, 1H), 4.17-4.28 (m, 2H), 2.46-2.57 (m, 2H), 2.02 (s, 3H),
1.52-1.73 (m, 3H), 1.31 (t, J ) 7.1 Hz, 3H), 0.89 (d, J ) 6.6
(R)-N-Acetyl-r-eth ylp r op ylglycin e Eth yl Ester (13b).
Compound 13b was prepared from 6b in a manner similar to
that described for the preparation of 12a . 13b: 48%. Com-
pound 6b was recovered in 42%. 13b: colorless crystals; mp
Hz, 3H), 0.77 (d, J ) 6.6 Hz, 3H), 0.70 (t, J ) 7.3 Hz, 3H); 13
C
NMR (CDCl3) δ 175.1, 168.8, 64.9, 61.7, 43.5, 29.1, 24.9, 24.2,
23.8, 22.7, 14.1, 8.1; FABMS m/z 230 (M+ + H). Anal. Calcd
for C12H23N1O3: C, 62.85; H, 10.11; N, 6.11. Found: C, 62.43;
H, 10.01; N, 6.33. The specific rotation of 13e prepared using
(R,R)-cyclohexane-1,2-diol showed [R]25D +21.2 (c 1.09, CHCl3).
44-45 °C (recryst. from hexane); [R]27 -15.6 (c 2.00, CHCl3);
D
IR (KBr) 3400 (br), 3300 (br), 1715, 1640 cm-1; 1H NMR
(CDCl3) δ 6.40 (br s, 1H), 4.23 (q, J ) 7.3 Hz, 2H), 2.41-2.60
(m, 2H), 2.01 (s, 3H), 1.60-1.82 (m, 2H), 1.29 (m, 1H), 1.30 (t,
J ) 7.3 Hz, 3H), 0.98 (m, 1H), 0.87 (t, J ) 7.0 Hz, 3H), 0.73 (t,
J ) 7.0 Hz, 3H); 13C NMR (CDCl3) δ 174.4, 168.8, 65.5, 61.7,
Ack n ow led gm en t. This work was partly supported
by a Grant-in-Aid for Encouragement of Young Scien-
tists from the Ministry of Education, Sports, Science and
Culture of J apan.
37.2, 28.1, 24.1, 17.6, 14.2, 13.9, 8.3; FABMS m/z 216 (M+
H). Anal. Calcd for C11H21N1O3: C, 61.37; H, 9.83; N, 6.51.
Found: C, 61.49; H, 9.84; N, 6.59.
+
(R)-N-Acetyl-r-bu tyleth ylglycin e Eth yl Ester (13c).
Compound 13c was prepared from 6c in a manner similar to
that described for the preparation of 12a : 13c: 37%. Com-
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
NMR spectra of all new compounds, and some 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
pound 6c was recovered in 50%. 13c: a colorless oil; [R]25
D
-16.37 (c 0.63, CHCl3); IR (neat) 3330 (br), 1740, 1660 cm-1
;
1H NMR (CDCl3) δ 6.40 (br s, 1H), 4.24 (q, J ) 7.2 Hz, 2H),
2.42-2.54 (m, 2H), 2.01 (s, 3H), 1.66-1.80 (m, 2H), 1.19-1.32
J O001423M