Stereochemical study on α-alkylation of β-branched α-amino acid derivatives via memory of chirality

Article abstract of DOI:10.1055/s-2005-865337

α-Alkylation of N-Boc-N-MOM amino acid derivatives with an additional chiral center at the β-carbon proceeded with retention of configuration, irrespective of the chirality at the β-carbon. The C-N axial chirality of the enolate intermediates played a decisive role in the stereochemical course of the alkylation, while the central chirality of the α-carbon had little effect. Amino acid derivatives with contiguous quaternary and tertiary stereocenters are readily obtained in a stereochemically expectable manner. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-865337

1368
FEATURE ARTICLE
Stereochemical Study on a-Alkylation of b-Branched a-Amino Acid
Derivatives via Memory of Chirality
a
-Alkylation of
a
b
-Branche
k
d
a
-
Amino
A
e
cids via
M
e
o
mory of Chirality Kawabata,* Jianyong Chen, Hideo Suzuki, Kaoru Fuji
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
Fax +81(774)383197; E-mail: kawabata@scl.kyoto-u.ac.jp
Received 21 March 2005
chiral nonracemic enolate A with a chiral C–N axis has
Abstract: a-Alkylation of N-Boc-N-MOM amino acid derivatives
with an additional chiral center at the b-carbon proceeded with re-
tention of configuration, irrespective of the chirality at the b-carbon.
The C–N axial chirality of the enolate intermediates played a deci-
been proposed as the crucial intermediate for this novel
asymmetric induction, whose racemization barrier is 16.0
kcal/mol (when R = CH2Ph). The corresponding half-life
sive role in the stereochemical course of the alkylation, while the of racemization is 22 hours at –78 °C.4 We further devel-
central chirality of the b-carbon had little effect. Amino acid deriv-
atives with contiguous quaternary and tertiary stereocenters are
readily obtained in a stereochemically expectable manner.
oped a route for the straightforward synthesis of cyclic
amino acids with a quaternary stereocenter from readily
available a-amino acids via memory of chirality
[Scheme 1, (2)].5 An axially chiral enolate intermediate B
was also proposed to be a crucial intermediate based on
several experimental evidence.5
Key words: axial chirality, amino acid, memory of chirality, eno-
late, quaternary stereocenter
In the course of study of asymmetric synthesis based on
memory of chirality, we became interested in the stereo-
chemistry of a-alkylation of b-branched a-amino acid de-
rivatives 1 that have chiral centers at C(2) and C(3)
(Scheme 2). If the chiral information at C(2) is lost with
formation of the enolate, the stereochemical course of a-
alkylation of 1 should be totally controlled by the chirality
at C(3). On the other hand, if the chirality of C(2) is pre-
served as C–N axial chirality as shown in C, the stereo-
chemical course should be affected by chirality both at
C(2) and C(3).
The stereoselective construction of chiral quaternary ste-
reocenters is one of the most challenging tasks in current
synthetic organic chemistry.1 We have developed a direct
method for the enantioselective construction of a,a-di-
substituted a-amino acids from usual a-amino acids via
memory of chirality.2,3 Under these conditions, a-meth-
ylation of N-tert-butoxycarbonyl(Boc)-N-methoxymeth-
yl(MOM)-a-amino acid derivatives takes place in up to
93% ee without the aid of external chiral sources such as
chiral auxiliaries or chiral catalysts [Scheme 1, (1)].4 A
OK
R
EtO
CO2Et
MOM
R
CO2Et
Boc
MOM
CH2OMe
i ) KHMDS
ii) MeI
N
t
(1)
(2)
CO2 Bu
N
R
Me
N
N
Boc
up to 93% ee
A
R
EtO2C
R
CO2Et
OK
KHMDS
EtO
(CH2)nBr
(CH2)n
N
Boc
N
t
(CH2)nBr
CO2 Bu
Boc
R
up to 98% ee
n = 2 ~ 5
B
Scheme 1
OK
2
Me
2
Me
3
EtO
R
R
CO2Et
MOM
R
CO2Et
Boc
MOM
CH2OMe
i ) KHMDS
ii) E-X
*
*
N
3
*
t
CO2 Bu
N
E
N
Boc
Me
1
2
C
Scheme 2
SYNTHESIS 2005, No. 8, pp 1368–1377
x
x
.
x
x
.2
0
0
5
Advanced online publication: 25.04.2005
DOI: 10.1055/s-2005-865337; Art ID: E13305SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biographical Sketches
a-Alkylation of b-Branched a-Amino Acids via Memory of Chirality
1369
Takeo Kawabata was born joined Sagami Chemical maceutical Society of Japan
in Osaka, Japan in 1955. He Research Center as a re- Award for Young Scientists
received his PhD in 1983 searcher (1985–1989). He in 1995. His research inter-
from Kyoto University un- was appointed as Assistant ests include asymmetric
der the guidance of Profes- Professor of the Institute for synthesis, enolate chemis-
sor Eiichi Fujita. After Chemical Research, Kyoto try, nucleophilic catalysis,
working as a postdoctoral University, in 1989 and pro- and structural and function-
fellow (1983–1985) at Indi- moted to Associate Profes- al investigation of hetero-
ana University with Profes- sor in 1998, and Professor in chiral oligomers.
sor Paul A. Grieco, he 2004. He received the Phar-
Jianyong Chen was born in University. He moved to Kaoru Fuji at the Institute of
1966 in Suzhou, Jiangsu, Shanghai Institute of Mate- Chemical Research, Kyoto
China. He obtained his BSc ria Medica, Chinese Acade- University, Japan. His re-
(medicinal chemistry) in my
of
Sciences
in search focused on asymmet-
1989 and MSc (medicinal September 1996 and re- ric synthesis based on
chemistry) in 1992 from ceived his PhD (organic memory of chirality. Since
China Pharmaceutical Uni- chemistry) in 1999. From 2001, he is working as a
versity. From 1992 to 1996 August 1999 to October postdoctoral fellow at Uni-
he worked at the Depart- 2001, he worked as a post- versity of Michigan, USA.
ment of Medicinal Chemis- doctoral fellow with Dr.
try of China Pharmaceutical Takeo Kawabata and Prof.
Hideo Suzuki was born in doctoral fellow at The Company, Osaka, Japan.
Osaka, Japan in 1970. He Scripps Research Institute, His research interests in-
received his PhD degree in USA, studying the total syn- clude asymmetric synthesis,
1998 from Kyoto University thesis of Everninomicins. natural product synthesis,
under the supervision of He moved to Array Bio- process chemistry, and drug
Professor Kaoru Fuji. He Pharma, Colorado, in 2000. discovery.
then joined Professor K. C. Since 2003, he is working
Nicolaou’s group as a post- for Takeda Pharmaceutical
Kaoru Fuji was born in Os- During that time, he joined Paris-Sud (1996) and at the
aka, Japan in 1938. He re- P. Gassman’s group at the Technical University of
ceived both his BA and PhD University of Minnesota as Vienna, Austria (2000). He
degrees from Kyoto Univer- a research fellow (1981– joined Otsuka Pharmaceuti-
sity. He was appointed As- 1982). Dr. Fuji has been a cal Company, Tokushima,
sistant Professor at the recipient of the Pharmaceu- as a counselor in 2002. In
Institute for Chemical Re- tical Society of Japan 2004, he moved to the
search, Kyoto University, in Award for Young Scientists Faculty of Pharmaceutical
1967. After a postdoctoral (1980) and of the Pharma- Sciences, Hiroshima Inter-
stay with James P. Kutney at ceutical Society of Japan national University, as a
the University of British Co- Award (1998), and held vis- dean. His research interests
lumbia in Canada (1971– iting positions at the Univer- include asymmetric synthe-
1973), he was promoted to sité Louis Pasteur de sis, natural product synthe-
Associate Professor in Strasbourg, France (1991 sis, and design and synthesis
1973, and Professor in 1983. and 1994), at the Université of artificial receptors.
Synthesis 2005, No. 8, 1368–1377 © Thieme Stuttgart · New York

1370
T. Kawabata et al.
FEATURE ARTICLE
The stereochemical question was examined with a pair of actly the same ratio and a combined yield of 90%. This in-
diastereomers, L-isoleucine derivative 3 and D-allo-iso- dicates that warming to 0 °C caused epimerization of the
leucine derivative 6 (Scheme 3).6 Treatment of 3 with 1.1 chiral C–N axis, leading to complete thermodynamic
mole equivalent of potassium hexamethyl disilazide (KH- equilibrium between D and E either from 3 or 6.7 The
MDS) in THF at –78 °C for 60 minutes followed by the half-life of epimerization of the chiral C–N axis in D and
addition of methyl iodide gave a mixture of diastereomers E is estimated to be shorter than one second at 0 °C, on the
4 and 5 in a 93:7 ratio and a combined yield of 93%. The assumption that the rotational barrier of the C–N axis in D
same treatment of 6 gave a mixture of 4 and 5 in a 14:86 and E is comparable to that of A (R = CH2Ph, 16.0 kcal/
ratio and a combined yield of 91%. The stereochemistry mol at –78 °C) and DS≠ of the restricted bond rotation is
of 5 was unambiguously determined to be (2R,3S) by an nearly zero.
X-ray crystallographic analysis of the corresponding p-ni-
Since the Boc and MOM groups at the nitrogen seem to be
essential for the generation of the C–N axial chirality, we
trobenzamide derivative.6 a-Methylation of both 3 and 6
occurred with retention of configuration at C(2). a-Meth-
next examined the reactions of the corresponding N,N-di-
ylation of 3 gave 4 as a major diastereomer whereas 6
Boc derivatives 7 and 10 that do not generate axially
gave 5 as a major diastereomer, although both 3 and 6
chiral enolates (Scheme 4).8 Upon a-methylation under
have an (S)-chiral center at C(3). Thus, chirality at C(2)
the conditions identical to those for alkylation of 3 and 6,
contributed decisively to the stereochemical course of the
7 afforded a mixture of 8 and 9 in a 54:46 ratio and 83%
a-methylation of 3 and 6 even in the presence of the adja-
cent chiral center C(3). We assume D (aS,3S) and E
(aR,3S) as the possible structures of chiral enolate inter-
mediates generated from 3 and 6, respectively, by analogy
with our recent results.2,3h,4,5 The C(2)–N axial chirality in
D and E played a predominant role in the stereochemical
course of a-methylation, while central chirality at C(3)
had little effect.
yield.9 The exactly same diastereomer ratio of 8 and 9 was
obtained in the a-methylation of 10 (97% yield). The ste-
reochemical course of the a-methylation of 7 and 10 was
totally controlled by the chirality at C(3), irrespective of
the chirality at C(2), which is in sharp contrast to the reac-
tions of 3 and 6. These results suggest that the reactions of
both 7 and 10 share a common enolate intermediate F.8
From the studies with isoleucine derivatives 3 and 6, it
could be concluded that the stereochemical course of the
a-methylation was controlled by the C–N axial chirality
derived from central chirality at C(2), while central chiral-
ity at C(3) had little effect.10 However, the effects of such
When 3 was treated with KHMDS in THF at –78 °C for
60 minutes and then at 0 °C for 30 minutes, the subse-
quent addition of methyl iodide at –78 °C gave a mixture
of 4 and 5 in a 40:60 ratio and a combined yield of 88%.
The same treatment of 6 gave a mixture of 4 and 5 in ex-
Me
Me
Me
OK
i) KHMDS, THF
ii) MeI, –78 °C
CO2Et
2
CO2Et
EtO
CO2Et
3
CH2OMe
N
+
t
3
2
Me
Me
N MOM
Boc
CO2 Bu
N MOM
Boc
N
MOM
Boc
Me
93%
93:7a
5
4
3
D (aS,3S)
(40:60)b
OK
2
Me
EtO
t
CO2Et
2
CO2 Bu
3
=
14:86a
(40:60)b
N
4:5
3
CH2OMe
N
MOM
Boc
Me
91%
6
E (aR,3S)
a) The enolate formation was performed at –78 °C for 1 h.
b) The enolate formation was performed at –78 °C for 1 h and then at 0 °C for 30 min.
Scheme 3
Me
Me
Me
i) KHMDS, THF
ii) MeI, –78 °C
83%
CO2Et
Boc
Boc
CO2Et
Boc
Boc
CO2Et
Boc
2
3
+
Me
Me
N
N
OK
2
N
Boc
EtO
t
CO2 Bu
7
54:46
8
9
N
t
3
CO2 Bu
Me
Me
CO2Et
Boc
3
8:9
=
54:46
2
F
N
Boc
97%
10
Scheme 4
Synthesis 2005, No. 8, 1368–1377 © Thieme Stuttgart · New York

FEATURE ARTICLE
a-Alkylation of b-Branched a-Amino Acids via Memory of Chirality
1371
a chiral center, that consists of ethyl, methyl, and hydro- THF at –78 °C for one hour followed by methyl iodide for
gen, on the stereochemical course of the a-alkylation must 20 hours to give a mixture of 16 and 17 in a 94:6 ratio and
be intrinsically very small, and it is estimated to be a combined yield of 92% (Scheme 6). The same treatment
DDG≠ = 0.06 kcal/mol based on the reactions of 7 and 10 of 18 gave a mixture of 16 and 17 in a 2:98 ratio and a
in Scheme 4. We then turned our attention to b-meth- combined yield of 93%. Thus, chirality at C(2) has a deci-
ylphenylalanine derivatives as substrates for further eluci- sive effect on the stereochemical course of the a-methyla-
dation because a chiral center consisting of phenyl, tion irrespective of the chirality of the adjacent C(3) chiral
methyl, and hydrogen is expected to show a more pro- center. We assume H (aR,3R) and I (aS,3R) as the possible
nounced effect on the stereochemistry of a-alkylation structures of chiral enolate intermediates generated from
(Scheme 5). At first, we examined reactions of N,N-di- 15 and 18, respectively. Comparing the stereoselectivity
Boc derivatives of b-methylphenylalanine, 11 and 14. of a-methylation of 15 and 18 to that of 19, which is lack-
Since they do not generate axially chiral enolates,11 the ing a chiral center at C(3), it might be expected that one of
diastereomeric ratio observed in the a-methylation should the diastereomers, 15 and 18, would show higher stereo-
be a measure of the effect of the C(3) chiral center. Upon selectivity (matched) than 19, the other would show lower
a-methylation under conditions identical to those for 7 stereoselectivity (mismatched) than 19. Surprisingly,
and 10, 11 gave a mixture of 12 and 13 in a 33:67 ratio and however, a-methylation of both 15 and 18 showed higher
in 84% yield. The exactly same diastereomer ratio of 12 stereoselectivity in their a-methylation than that of 19.
and 13 was obtained from 14, the C(2)-epimer of 11. The This would be resulting from higher stereochemical purity
stereochemical course was totally controlled by the chiral- of C–N axial chirality in H and I compared to J and/or the
ity at C(3), independent of the chirality at C(2). These re- higher face selectivity in the reactions of H and I with
sults again suggest that the reactions of both 11 and 14 methyl iodide compared to that of J.
share a common enolate intermediate G.11 The effect of
The corresponding reactions using racemates of 15 and 18
the C(3) chiral center in 11 and 14 was estimated to be
were examined. a-Methylation of rac-15 (anti) under the
DDG≠ = 0.27 kcal/mol based on the ratio (33:67) and it is
same conditions as applied for (2R,3R)-15 gave racemic
significantly larger than that of 7 and 10. Then, a-meth-
16 and 17 in a 94:6 ratio and a combined yield of 93%.
ylation of N-Boc-N-MOM-b-methylphenylalanine deriv-
Similarly, a-methylation of rac-18 (syn) gave racemic 16
ative 15 was performed by treatment with KHMDS in
Me
Me
Me
3
i) KHMDS, THF
ii) MeI, –78 °C
CO2Et
Boc
Boc
CO2Et
Boc
Boc
CO2Et
2
Ph
Me
Ph
Me
Ph
+
N
N
OK
2
N
Boc
Boc
EtO
t
CO2 Bu
33 : 67
70%
12
13
N
11
Me
t
3
Ph
CO2 Bu
Me
CO2Et
2
3
Ph
Boc
12 : 13 = 33 : 67
G
N
Boc
84%
14
Scheme 5
Me
Me
3
Me
OK
2
i) KHMDS, THF
ii) MeI, –78 °C
CO2Et
CO2Et
2
CO2Et
EtO
t
Ph
+
CO2 Bu
Ph
Ph
Me
N
Me
3
N MOM
Boc
N MOM
Boc
Ph
CH2OMe
N
MOM
Boc
Me
17
94:6
16
15
92%
H (aR,3R)
OK
Me
EtO
CO2Et
Boc
CH2OMe
3
Ph
16:17 = 2:98
N
2
t
3
2
Ph
CO2 Bu
N
MOM
Me
93%
18
I (aS,3R)
OK
3
i) KHMDS
CO2Et
CO2Et
Boc
CO2Et
EtO
Ph
Ph
+
CH2OMe
Ph
Ph
Me
N
t
Me
N MOM
Boc
N MOM
Boc
toluene–THF
(4:1)
ii) MeI, –78 °C
CO2 Bu
N
MOM
90:10
21
20
19
J (aS)
96%
Scheme 6
Synthesis 2005, No. 8, 1368–1377 © Thieme Stuttgart · New York

1372
T. Kawabata et al.
FEATURE ARTICLE
and 17 in a 3:97 ratio and a combined yield of 91%. No
significant difference in the stereochemistry of alkylation
was observed between optically pure and racemic sub-
strates. These results indicate that the aggregate structure
of intermediary enolates does not significantly contribute
to the stereochemical course of alkylation of 15 and 18,
which is in contrast to the case of 19.3h In order to gain in-
sight into the effect of the aggregate structure of enolate
intermediates on stereoselectivity, solvent effects on the
a-methylation of 3, 6, and 19 were examined. a-Methyla-
tion of 19 proceeded with the highest enantioselectivity in
toluene–THF (4:1) to give 20 and 21 in a 90:10 ratio,
while a 67:33 ratio was observed in THF.3h A much di-
minished solvent effect was observed in the a-methyla-
tion of 3 and 6. a-Methylation of 3 and 6 in THF gave 4
and 5 in ratios of 93:7 and 14:86, respectively, as already
described in Scheme 3, while in toluene–THF (4:1) 4 and
5 were obtained in ratios of 91:9 and 12:88 from 3 and 6,
respectively. These results led us to suggest that the aggre-
gate structure of an enolate generated from 19 contributes
significantly to the stereochemical course of a-alkylation,
while a similar effect is not observed for the a-alkylation
of 3 and 6.
Me
3
Me
i) KHMDS, THF
ii) MeI, –78 °C
CO2Bn
2
CO2Bn
Ph
Ph
Me
N MOM
Boc
N
MOM
Boc
93%
23
22
single diastereomer
Me
CO2Bn
Boc
3
Ph
MOM
recovery
2
N
24
Scheme 7
was further confirmed by NOE measurements carried out
with the corresponding tetrahydroisoquinoline derivatives
27 and 28, respectively (Figure 2). Removal of the nitro-
gen substituents of a 94:6 mixture of 16 and 17 by treat-
ment with 4 M HCl in ethyl acetate followed by Pictet–
Spengler reaction gave, after purification by column chro-
matography, diastereomerically pure 27. Similarly, a 2:98
mixture of 16 and 17 was transformed into diastereomer-
ically pure 28.13 NOE’s between C(3)-Me/C(4)-H and
C(3)-Me/C(4)-Me were observed in 27, which is consis-
tent with the most stable conformation K generated by
molecular modeling of 27 with MM3* force field.14 syn-
Orientation between C(3)-Me and C(4)-H in 28 was indi-
cated by the observation of the strong NOE in between,
which is consistent with the most stable conformation L
with the 3,4-dimethyl groups in diaxial conformation.14
Complete control of the stereochemistry of a-methylation
was achieved using the corresponding benzyl ester deriv-
ative 22. a-Methylation of 22 under the standard condi-
tions gave 23 as the only detectable product in 93% yield,
while the reaction of 24 resulted in total recovery
(Scheme 7).
Me
Me
Determination of the stereochemistry in 12, 13, 16, and 17
was achieved by their transformation into either 25 or
26.12 Treatment of a 94:6 mixture of 16 and 17 obtained
from the reaction of 15 with 6 M HCl at 100 °C followed
by purification with ion exchange resin gave a 94:6 mix-
ture of 25 and 26. The stereochemistry of 25 and 26 thus
obtained was determined by comparison of the 1H NMR
spectral data with those reported in the literature.12 Simi-
larly, the stereochemistry in 12 and 13 was determined by
the transformation into 25 and 26, respectively (Figure 1).
CO2H
NH2
CO2H
NH2
Ph
Me
Ph
Me
25
26
Figure 1
In conclusion, a-alkylation of b-branched N-Boc-N-
MOM-a-amino acid derivatives proceeded in retention of
the configuration, irrespective of the chirality at the b-car-
bon. The stereochemical course of the alkylation was con-
trolled by the C–N axial chirality derived from central
chirality at the a-carbon, while central chirality at the b-
carbon had little effect. This provides a straightforward
method for the preparation of amino acid derivatives with
Although the stereochemistry in 12, 13, 16, and 17 could
be assigned based on the transformation into the known
amino acids, 25 and 26, some ambiguity remained be-
cause of no obvious difference between the 1H NMR spec-
tra of 25 and 26.12 Thus, the stereochemistry in 16 and 17
Figure 2 NOE’s observed in 27 and 28 and their most stable conformations K and L. Hydrogen atoms, except C(3)-Me, C(4)-Me, and C(4)-
H, in K and L are omitted for clarity.
Synthesis 2005, No. 8, 1368–1377 © Thieme Stuttgart · New York

FEATURE ARTICLE
a-Alkylation of b-Branched a-Amino Acids via Memory of Chirality
1373
(2R,3S)-N-tert-Butoxycarbonyl-allo-isoleucine Ethyl Ester
contiguous quaternary and tertiary stereocenters in a ste-
reochemically expectable manner.15,16
Prepared from (2R,3S)-allo-isoleucine ethyl ester hydrochloride ac-
cording to the procedure for (2S,3S)-N-(tert-butoxycarbonyl)iso-
leucine ethyl ester in 96% yield.
[a]D19 –17 (c 1.2, CHCl3).
Melting points were measured using a Yanagimoto micro point ap-
paratus and are uncorrected. NMR spectra were obtained with a
Varian Gemini 200 (200 MHz) spectrometer or a JEOL JMN-GX
400 spectrometer, with chemical shifts given in ppm (internal stan-
dards: TMS or CHCl3, indicating 0 or 7.24, respectively). IR spectra
were recorded on a JASCO FT/IR-300 spectrometer. Specific rota-
tions were measured with a Horiba SEPA-200 automatic digital po-
larimeter. Mass spectra were recorded on a JEOL JMS-DX300
mass spectrometer. TLC analyses and preparative TLC were per-
formed on commercial glass plates bearing a 0.25 mm layer or a 0.5
mm layer of Merck Kiesel gel 60 F254, respectively. Silica gel col-
umn chromatography was carried out with Wakogel C-200, Fuji
Silysia BW-1277H, or Nacalai Tesque Silica gel 60 (150–325
mesh). Dry solvents (THF, Et2O, hexane, CH2Cl2, and toluene; <50
ppm water contents) were purchased from Kanto Chemical Co., Inc.
and used without further treatment.
IR (neat): 3373, 2971, 2935, 1716, 1505, 1458, 1367 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.98 (d, J = 9.2 Hz, 1 H), 4.34 (dd,
J = 3.6, 9.2 Hz, 1 H), 4.25–4.14 (m, 2 H), 1.96–1.85 (m, 1 H), 1.50–
1.40 (m, 1 H), 1.45 (s, 9 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.23–1.15 (m,
1 H), 0.95 (t, J = 7.3 Hz, 3 H), 0.84 (d, J = 7.0 Hz, 3 H).
MS (EI): m/z (%) = 259 (M+), 244, 214, 203, 186, 158, 147, 130.
Anal. Calcd for C13H25NO4: C, 60.21; H, 9.72; N, 5.40. Found: C,
60.04; H, 9.88; N, 5.39.
(2R,3S)-N-tert-Butoxycarbonyl-N-methoxymethyl-allo-isoleu-
cine Ethyl Ester (6)
Prepared from (2R,3S)-N-tert-butoxycarbonyl-allo-isoleucine ethyl
ester according to the procedure for 3 in 78% yield.
[a]D19 +48 (c 1.2, CHCl3).
IR (neat): 2974, 1745, 1705, 1367, 1295, 1176, 1086 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.84–4.67 (m, 2 H), 4.26 (br d,
J = 8.7 Hz, 0.5 H), 4.20–4.10 (m, 2 H), 3.86 (br d, J = 9.0 Hz, 0.5
H), 3.35, 3.32 (2 br s, 3 H), 2.23–2.09 (m, 1 H), 1.62–1.51 (m, 1 H),
1.46 (s, 9 H), 1.27 (br t, J = 6.3 Hz, 3 H), 1.20–1.07 (m, 1 H), 0.93
(t, J = 7.3 Hz, 3 H), 0.88 (d, J = 7.0 Hz, 3 H).
(2S,3S)-N-tert-Butoxycarbonyl-N-(methoxymethyl)isoleucine
Ethyl Ester (3)
N,N-Diisopropylethylamine (6.97 mL, 40mmol) and di-tert-butyl
dicarbonate (4.80 g, 22 mmol) were added to a solution of (2S,3S)-
isoleucine ethyl ester hydrochloride (3.91 g, 20 mmol) in CH2Cl2
(40 mL) at 0 °C. The mixture was warmed to r.t. and stirred for 20
h, then poured into sat. aq NH4Cl (50 mL) and extracted with EtOAc
(300 mL). The organic layer was washed with sat. aq NaHCO3 (30
mL) and brine (30 mL), dried over anhyd Na2SO4, filtered, and con-
centrated in vacuo. The residue was purified by flash column chro-
matography (SiO2, EtOAc–hexane, 1:9) to give (2S,3S)-N-(tert-
butoxycarbonyl)isoleucine ethyl ester as a colorless oil (5.13 g, 99%
yield).
MS (EI): m/z (%) = 303 (M+), 272, 247, 230, 202, 172, 146, 130.
Anal. Calcd for C15H29NO5: C, 59.38; H, 9.63; N, 4.62. Found: C,
59.33; H, 9.76; N, 4.57.
[a]D19 +16 (c 1.0, CHCl3).
IR (neat): 3371, 2971, 2935, 1715, 1505, 1456, 1367 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.04 (d, J = 7.8 Hz, 1 H), 4.26–
4.13 (m, 3 H), 1.89–1.80 (m, 1 H), 1.48–1.39 (m, 1 H), 1.45 (s, 9 H),
1.28 (t, J = 7.2 Hz, 3 H), 1.23–1.12 (m, 1 H), 0.93 (d, J = 6.8 Hz, 3
H), 0.92 (t, J = 7.3 Hz, 3 H).
a-Methylation of 3: (2S,3S)- and (2R,3S)-N-tert-Butoxycarbon-
yl-N-methoxymethyl-a-methylisoleucine Ethyl Esters (4 and 5),
and (2S,3S)-N-p-Nitrobenzoyl-a-methylisoleucine Ethyl Ester
A solution of 3 (dried azeotropically with toluene prior to use, 152
mg, 0.5 mmol) in THF (4.5 mL) was added to a solution of
KHMDS17 (0.50 M in THF, 1.1 mL, 0.55 mmol) at –78 °C. After 60
min, MeI (0.31 mL, 5.0 mmol) was added and the mixture was
stirred at –78 °C for 20 h, then poured into sat. aq NH4Cl (20 mL)
and extracted with EtOAc (150 mL). The organic layer was washed
with sat. aq NaHCO3 (20 mL) and brine (20 mL), dried over anhyd
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (SiO2, EtOAc–hexane, 1:12)
to give an inseparable mixture (154 mg) of 4 and 5, and a trace
amount (≤4%) of 3. The combined yield of 4 and 5 and the diaste-
reomeric ratio were determined by 400 MHz 1H NMR spectroscopy
to be 93% and 93:7, respectively.
1H NMR (400 MHz, CDCl3): d = 5.12, 5.08 (2 d, J = 11.8, 11.7 Hz,
ratio = 1:<10, 1 H), 4.58, 4.53 (2 d, J = 11.7, 11.8 Hz, ratio = 93:7,
1 H), 4.20–4.06 (m, 2 H), 3.36, 3.35 (2 s, ratio = 93:7, 3 H), 2.37–
2.17 (m, 1 H), 1.92–1.80, 1.55–1.42 (2 m, ratio = 1:>10, 1 H), 1.49
(s, 3 H), 1.45 (s, 9 H), 1.26, 1.25 (2 t, J = 7.3, 7.3 Hz, ratio = >10:1,
3 H), 1.02, 0.84 (2 d, J = 6.6, 6.8 Hz, ratio = 93:7, 3 H), 1.00–0.85
(m, 1 H), 0.92 (t, J = 7.2 Hz, 3 H).
MS (EI): m/z (%) = 259 (M+), 244, 214, 203, 186, 158, 147, 130.
Anal. Calcd for C13H25NO4: C, 60.21; H, 9.72; N, 5.40. Found: C,
59.94; H, 9.80; N, 5.34.
Potassium hexamethyldisilazide (KHMDS)17 (0.46 M in THF, 12.3
mL, 5.7 mmol) was added to a solution of (2S,3S)-N-(tert-butoxy-
carbonyl)isoleucine ethyl ester (1.55 g, 6.0 mmol) in THF (5 mL) at
–78 °C. After 30 min, chloromethyl methyl ether (1.37 mL, 18
mmol) was added and the mixture was gradually warmed to r.t. dur-
ing a period of 20 h. The mixture was poured into sat. aq NH4Cl (50
mL) and extracted with EtOAc (300 mL). The organic layer was
washed with sat. aq NaHCO3 (30 mL) and brine (30 mL), dried over
anhyd Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography (SiO2, Et2O–hexane, 1:9)
to give 3 as a colorless oil (1.68 g, 93% yield).
[a]D19 –44 (c 1.0, CHCl3).
IR (neat): 2978, 1742, 1707, 1367, 1300, 1255, 1143, 1083 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.86–4.67 (m, 2 H), 4.33 (br m,
0.5 H), 4.21–4.10 (m, 2 H), 3.92 (br d, J = 8.1 Hz, 0.5 H), 3.34 (br
s, 3 H), 2.14–1.98 (m, 1 H), 1.56–1.39 (m, 1 H), 1.47 (s, 9 H), 1.27
(t, J = 7.0 Hz, 3 H), 1.15–1.01 (m, 1 H), 0.97 (d, J = 6.8 Hz, 3 H),
0.90 (t, J = 7.3 Hz, 3 H).
MS (EI): m/z (%) = 317 (M+), 286, 260, 244, 216, 186, 160, 140,
112.
Exact mass calcd for C16H31NO5: 317.2202; found: m/z 317.2217.
An analytically pure sample of the mixture of 4 and 5 was obtained
by removing the trace amount of 3 through selective ester hydroly-
sis (10% KOH/dioxane = 4:1, Bu4NI, 50 °C). The diastereomeric
ratio of 4 to 5 did not alter before and after hydrolysis.
MS (EI): m/z (%) = 303 (M+), 272, 247, 230, 202, 172, 146, 130.
IR (neat): 2976, 1740, 1702, 1409, 1367, 1299, 1252, 1173, 1104,
1084 cm–1.
Anal. Calcd for C15H29NO5: C, 59.38; H, 9.63; N, 4.62. Found: C,
59.18; H, 9.82; N, 4.61.
Synthesis 2005, No. 8, 1368–1377 © Thieme Stuttgart · New York

1374
T. Kawabata et al.
FEATURE ARTICLE
Anal. Calcd for C16H31NO5: C, 60.54; H, 9.84; N, 4.41. Found: C,
60.58; H, 9.99; N, 4.40.
residue was purified by flash column chromatography (SiO2, Et2O–
hexane, 1:15) to give 7 as a colorless oil (710 mg, 66% yield).
The mixture (120 mg) was dissolved in 4 M HCl in EtOAc (3 mL)
and the solution was stirred at r.t. for 1 h. After concentration in vac-
uo, the residue was dissolved in CH2Cl2 (2 mL) and treated with
N,N-diisopropylethylamine (0.20 mL, 1.1 mmol) and p-nitroben-
zoyl chloride (140 mg, 0.76 mmol) at r.t. for 4 h. Work-up followed
by purification by flash column chromatography (CHCl3–acetone,
60:1) gave a mixture of (2S,3S)- and (2R,3S)-N-p-nitrobenzoyl-a-
methylisoleucine ethyl ester (110 mg, 94% yield). Recrystallization
from Et2O–hexane (2:1) gave diastereomerically and analytically
pure (2S,3S)-N-p-nitrobenzoyl-a-methylisoleucine ethyl ester.
[a]D19 –43 (c 1.0, CHCl3).
IR (neat): 2979, 1748, 1705, 1456, 1368, 1311, 1237, 1130 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.53 (d, J = 9.5 Hz, 1 H), 4.15 (q
of ABq, JAB = 10.7 Hz, JAX = 7.0 Hz, DnAB = 14.4 Hz, 2 H), 2.29–
2.22 (m, 1 H), 1.49 (s, 18 H), 1.48–1.38 (m, 1 H), 1.25 (t, J = 7.0
Hz, 3 H), 1.10 (d, J = 6.5 Hz, 3 H), 1.07–0.99 (m, 1 H), 0.88 (t,
J = 7.4 Hz, 3 H).
1H NMR (400 MHz, C6D6): d = 4.87 (d, J = 9.4 Hz, 1 H), 3.96 (q of
ABq, JAB = 10.9 Hz, JAX = 7.0 Hz, JAB = 23.8 Hz, 2 H), 2.58–2.51
(m, 1 H), 1.67–1.59 (m, 1 H), 1.40 (s, 18 H), 1.27–1.22 (m, 1 H),
1.20 (d, J = 6.5 Hz, 3 H), 0.96 (t, J = 7.0 Hz, 3 H), 0.88 (t, J = 7.3
Hz, 3 H).
Colorless needles (ether–hexane), mp 135–136 °C.
[a]D18 +14 (c 1.1, CHCl3).
IR (KBr): 3439, 2971, 1728, 1663, 1603, 1525, 1510, 1482 cm–1.
1H NMR (400 MHz, acetone-d6): d = 8.30 (d, J = 8.7 Hz, 2 H), 8.05
(d, J = 8.7 Hz, 2 H), 7.96 (br s, 1 H), 4.15 (q of ABq, JAB = 10.7 Hz,
JAX = 7.0 Hz, DnAB = 15.9 Hz, 2 H), 1.98–1.83 (m, 2 H), 1.56 (s, 3
H), 1.22 (t, J = 7.0 Hz, 3 H), 1.18–1.10 (m, 1 H), 0.96 (t, J = 7.2 Hz,
3 H), 0.94 (d, J = 6.8 Hz, 3 H).
MS (EI): m/z (%) = 359 (M+), 303, 286, 258, 247, 202, 186, 147,
130.
Anal. Calcd for C18H33NO6: C, 60.14; H, 9.25; N, 3.90. Found: C,
59.94; H, 9.37; N, 3.90.
(2R,3S)-N,N-Bis(tert-butoxycarbonyl)-allo-isoleucine Ethyl
Ester (10)
MS (EI): m/z (%) = 322 (M+), 293, 277, 265, 249, 219, 167, 150,
134, 104, 92, 76.
Prepared from (2R,3S)-N-(tert-butoxycarbonyl)-allo-isoleucine
ethyl ester according to the procedure for 7 in 85% yield.
[a]D19 +41 (c 1.0, CHCl3).
Anal. Calcd for C16H22N2O5: C, 59.62; H, 6.88; N, 8.69. Found: C,
59.60; H, 6.99; N, 8.66.
IR (neat): 2979, 1747, 1456, 1368, 1314, 1235, 1132 cm–1.
a-Methylation of 6: (2R,3S)-N-p-Nitrobenzoyl-a-methyl-allo-
isoleucine Ethyl Ester
1H NMR (400 MHz, CDCl3): d = 4.56 (d, J = 9.2 Hz, 1 H), 4.15 (q
of ABq, JAB = 10.9 Hz, JAX = 7.1 Hz, DnAB = 14.2 Hz, 2 H), 2.33–
2.26 (m, 1 H), 1.82–1.72 (m, 1 H), 1.49 (s, 18 H), 1.25 (t, J = 7.1
Hz, 3 H), 1.21–1.16 (m, 1 H), 0.95 (t, J = 7.5 Hz, 3 H), 0.84 (d,
J = 7.0 Hz, 3 H).
1H NMR (400 MHz, C6D6): d = 4.88 (d, J = 9.0 Hz, 1 H), 3.97 (q of
ABq, JAB = 10.9 Hz, JAX = 7.2 Hz, DnAB = 26.2 Hz, 2 H), 2.61–2.54
(m, 1 H), 1.96–1.87 (m, 1 H), 1.39 (s, 18 H), 1.36–1.23 (m, 1 H),
0.98 (d, J = 7.0 Hz, 3 H), 0.97 (t, J = 7.2 Hz, 3 H), 0.96 (t, J = 7.5
Hz, 3 H).
a-Methylation of 6 was performed according to the procedure for
the methylation of 3. The reaction residue was purified by flash col-
umn chromatography (SiO2, EtOAc–hexane, 1:12) to give an insep-
arable mixture (154 mg) of 4 and 5, and a trace amount (≤6%) of 6.
The combined yield of 4 and 5 and the diastereomeric ratio were de-
termined by 400 MHz 1H NMR spectroscopy to be 91% and 14:86,
respectively. The mixture (129 mg) was treated with 4 M HCl in
EtOAc followed by p-nitrobenzoyl chloride to give a mixture of
(2S,3S)- and (2R,3S)-N-p-nitrobenzoyl-a-methylisoleucine ethyl
ester (118 mg, 90% yield). Recrystallization from Et2O–hexane
(2:1) gave diastereomerically and analytically pure (2R,3S)-N-p-ni-
trobenzoyl-a-methylisoleucine ethyl ester.
MS (EI): m/z (%) = 359 (M+), 303, 286, 258, 247, 202, 186, 147,
130.
Anal. Calcd for C18H33NO6: C, 60.14; H, 9.25; N, 3.90. Found: C,
59.98; H, 9.38; N, 4.01.
Colorless prisms (ether–hexane), mp 129–130 °C.
[a]D18 –17 (c 1.0, CHCl3).
IR (KBr): 3437, 2973, 1727, 1663, 1523, 1482 cm–1.
(2R,3R)-N,N-Bis(tert-butoxycarbonyl)-b-methylphenylalanine
Ethyl Ester (11)
1H NMR (400 MHz, acetone-d6): d = 8.30 (d, J = 8.7 Hz, 2 H), 8.06
(d, J = 8.7 Hz, 2 H), 7.88 (s, 1 H), 4.15 (q of ABq, JAB = 10.7 Hz,
JAX = 7.0 Hz, DnAB = 7.6 Hz, 2 H), 2.04–1.97 (m, 1 H), 1.68–1.61
(m, 1 H), 1.58 (s, 3 H), 1.22 (t, J = 7.0 Hz, 3 H), 1.13–1.09 (m, 1 H),
1.07 (d, J = 6.8 Hz, 3 H), 0.92 (t, J = 7.2 Hz, 3 H).
MS (EI): m/z (%) = 322 (M+), 293, 277, 265, 249, 219, 167, 150,
134, 104, 92, 76.
Potassium hexamethyldisilazide (KHMDS)17 (0.53 M in THF, 1.81
mL, 0.95 mmol) was added to a solution of (2R,3R)-N-tert-butoxy-
carbonyl-b-methylphenylalanine ethyl ester (307mg, 1.0 mmol)18 in
THF (5 mL) at –78 °C. After 30 min, di-tert-butyl dicarbonate (436
mg, 2.0 mmol) was added and the mixture was gradually warmed to
r.t. during a period of 20 h. The mixture was poured into aq NH4Cl
(20 mL) and extracted with EtOAc (150 mL). The organic layer was
washed with brine (20 mL), dried over anhyd Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography (SiO2, Et2O–hexane, 1:15) to give 11 (273 mg,
67% yield) as a colorless oil.
Anal. Calcd for C16H22N2O5: C, 59.62; H, 6.88; N, 8.69. Found: C,
59.50; H, 6.96; N, 8.44.
(2S,3S)-N,N-Bis(tert-butoxycarbonyl)isoleucine Ethyl Ester (7)
Potassium hexamethyldisilazide (KHMDS)17 (0.51 M in THF, 5.56
mL, 2.8 mmol) was added to a solution of (2S,3S)-N-(tert-butoxy-
carbonyl)isoleucine ethyl ester (777 mg, 3.0 mmol) in THF (20 mL)
at –78 °C. After 30 min, di-tert-butyl dicarbonate (1.31 g, 6.0
mmol) was added and the mixture was gradually warmed to r.t. dur-
ing a period of 20 h. The reaction mixture was poured into sat. aq
NH4Cl (30 mL) and extracted with EtOAc (150 mL). The organic
layer was washed with sat. aq NaHCO3 (30 mL) and brine (30 mL),
dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The
[a]D20 +67 (c 1.1, CHCl3).
IR (neat): 2980, 2934, 1748, 1455, 1367, 1260, 1130, 1029 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.23–7.11 (m, 5 H), 4.97 (d,
J = 10.0 Hz, 1 H), 4.29–4.12 (m, 2 H), 3.63–3.52 (m, 1 H), 1.50 (d,
J = 6.8 Hz, 3 H), 1.37 (s, 18 H), 1.26 (t, J = 7.0 Hz, 3 H).
1H NMR (400 MHz, C6D6): d = 7.30–7.01 (m, 5 H), 5.32 (d,
J = 10.0 Hz, 1 H), 4.08–3.90 (m, 3 H), 1.59 (d, J = 6.8 Hz, 3 H),
1.29 (s, 18 H), 0.96 (t, J = 7.0 Hz, 3 H).
Synthesis 2005, No. 8, 1368–1377 © Thieme Stuttgart · New York

FEATURE ARTICLE
a-Alkylation of b-Branched a-Amino Acids via Memory of Chirality
1375
MS (EI): m/z (%) = 407 (M+), 351, 306, 295, 250, 234, 202, 190,
MS (EI): m/z (%) = 351 (M+), 320, 278, 246, 220, 190, 178, 146,
146, 141.
105.
Anal. Calcd for C22H33NO6: C, 64.84; H, 8.16; N, 3.44. Found: C,
64.97; H, 8.13; N, 3.35.
Anal. Calcd for C19H29NO5: C, 64.94; H, 8.32; N, 3.99. Found: C,
64.74; H, 8.44; N, 4.03.
(2S,3R)-N,N-Bis(tert-butoxycarbonyl)-b-methylphenylalanine
Ethyl Ester (14)
Prepared from (2S,3R)-N-tert-butoxycarbonyl-b-methylphenylala-
nine ethyl ester18 according to the procedure for (2R,3R)-N,N-
bis(tert-butoxycarbonyl)-b-methylphenylalanine ethyl ester in 77%
yield.
[a]D20 –75 (c 1.2, CHCl3).
IR (neat): 2979, 1795, 1749, 1455, 1368, 1234, 1148, 1038 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.38–7.13 (m, 5 H), 5.17 (d,
J = 9.9 Hz, 1 H), 4.09–3.94 (m, 2 H), 3.70–3.58 (m, 1 H), 1.55 (s,
18 H), 1.17 (d, J = 7.3 Hz, 3 H), 1.12 (t, J = 7.0 Hz, 3 H).
1H NMR (400 MHz, C6D6): d = 7.54–7.02 (m, 5 H), 5.59 (d, J = 9.9
Hz, 1 H), 4.03–3.93 (m, 1 H), 3.86–3.67 (m, 2 H), 1.42 (s, 18 H),
1.35 (d, J = 7.3 Hz, 3 H), 0.76 (t, J = 7.0 Hz, 3 H).
(2S,3R)-N-tert-Butoxycarbonyl-N-methoxymethyl-b-methyl-
phenylalanine Ethyl Ester (18)
Prepared from (2S,3R)-N-tert-butoxycarbonyl-b-methylphenylala-
nine ethyl ester18 according to the procedure for 15 in 72% yield.
[a]D20 –72.3 (c 1.2, CHCl3).
IR (neat): 2977, 1714, 1455, 1368, 1144, 1084 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.34–7.10 (m, 5 H), 4.86, 4.79 (2
br s, ratio = 1:1, 2 H), 4.70, 4.39 (2 br s, ratio = 1:1, 1 H), 3.94 (br
s, 2 H), 3.49 (br s, 1 H), 3.38 (br s, 3 H), 1.52 (s, 9 H), 1.25 (d,
J = 7.0 Hz, 3 H), 1.07, 0.98 (2 br s, ratio = 1:1, 3 H).
MS (EI): m/z (%) = 351 (M+), 320, 278, 246, 220, 190, 178, 146,
105.
Anal. Calcd for C19H29NO5: C, 64.94; H, 8.32; N, 3.99. Found: C,
64.93; H, 8.48; N, 3.93.
MS (EI): m/z (%) = 407 (M+), 351, 306, 295, 250, 234, 202, 190,
146, 141.
a-Methylation of 15: A 94:6 Mixture of (2R,3R)- and (2S,3R)-N-
tert-Butoxycarbonyl-N-methoxymethyl-a,b-dimethylphenylala-
nine Ethyl Esters (16 and 17)
Anal. Calcd for C22H33NO6: C, 64.84; H, 8.16; N, 3.44. Found: C,
64.64; H, 8.18; N, 3.41.
A solution of 15 (dried azeotropically with toluene prior to use, 176
mg, 0.50 mmol) in THF (4.5 mL) was added to a solution of
KHMDS (0.50 M in THF, 1.1 mL, 0.55 mmol) at –78 °C. After 60
min, MeI (0.31 mL, 5.0 mmol) was added and the mixture was
stirred at –78 °C for 20 h, then poured into aq NH4Cl (20 mL) and
extracted with EtOAc (150 mL). The organic layer was washed with
brine (30 mL), dried over anhyd Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by flash column chromatography
(SiO2, Et2O–hexane, 1:10) to give an inseparable mixture (168 mg)
of 16 and 17, and a trace amount of 15. The combined yield of 16
and 17 and the diastereomeric ratio were determined by 400 MHz
1H NMR spectroscopy to be 92% and 94:6, respectively.
[a]D20 +128 (c 1.0, CHCl3).
IR (neat): 2978, 1742, 1698, 1455, 1376, 1297 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.32–7.10 (m, 5 H), 4.41–3.83 (m,
4 H), 3.41–3.28 (m, 1 H), 3.34, 3.18 (2 s, ratio = 6:94, 3 H), 1.57 (s,
3 H), 1.54 (d, J = 7.0 Hz, 3 H), 1.49 (s, 9 H), 1.27 (t, J = 6.8 Hz, 3
H).
a-Methylation of 11: A 33:67 Mixture of (2R,3R)- and (2S,3R)-
N,N-Bis(tert-butoxycarbonyl)-a,b-dimethylphenylalanineEthyl
Esters (12 and 13)
a-Methylation of 11 was performed according to the procedure for
a-methylation of 3. The residue was purified by flash column chro-
matography (SiO2, Et2O–hexane, 1:10) to yield an inseparable mix-
ture (196 mg) of 12 and 13, and a trace amount of 11. The combined
yield of 12 and 13 and the diastereomeric ratio were determined by
400 MHz 1H NMR spectroscopy to be 84% and 33:67, respectively.
IR (neat): 2978, 1745, 1715, 1455, 1339, 1127 cm–1.
1H NMR (400 MHz, C6D6): d = 7.60–7.02 (m, 5 H), 4.30–3.88 (m,
3 H), 1.80, 1.60 (2 s, ratio = 33:67, 3 H), 1.72, 1.58 (2 d, J = 7.5, 7.7
Hz, ratio = 33:67, 3 H), 1.54, 1.45 (2 s, ratio = 33:67, 18 H), 0.96,
0.93 (2 d, J = 7.7, 7.2 Hz, ratio = 67:33, 3 H).
MS (EI): m/z (%) = 421 (M+, 1), 348 (5), 316 (50), 264 (50), 216
(60), 192 (60), 160 (100).
Exact mass calcd for C23H35NO6: 421.2465; found: m/z 421.2469.
MS (EI): m/z (%) = 365 (M+), 351, 334, 292, 277, 260, 234, 204,
192, 160, 128.
(2R,3R)-N-tert-Butoxycarbonyl-N-methoxymethyl-b-methyl-
phenylalanine Ethyl Ester (15)
Exact mass calcd for C20H31NO5: 365.2202; found: m/z 365.2178.
Potassium hexamethyldisilazide (KHMDS)17 (0.53 M in THF,
3.01mL, 1.59 mmol) was added to a solution of (2R,3R)-N-tert-but-
oxycarbonyl-b-methylphenylalanine ethyl ester (512 mg, 1.67
mmol)18 in THF (6 mL) at –78 °C. After 30 min, chloromethyl me-
thyl ether (0.38 mL, 5.00 mmol) was added and the mixture was
gradually warmed to r.t. during a period of 20 h. The mixture was
poured into aq NH4Cl (20 mL) and extracted with EtOAc (150 mL).
The organic layer was washed with brine (20 mL), dried over anhyd
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (SiO2, Et2O–hexane, 1:12) to
give 15 (472mg, 81% yield) as a colorless oil.
a-Methylation of 18: A 2:98 Mixture of (2R,3R)- and (2S,3R)-N-
tert-Butoxycarbonyl-N-methoxymethyl-a,b-dimethylphenylala-
nine Ethyl Esters (16 and 17)
a-Methylation of 18 was performed according to the procedure for
a-methylation of 15. The residue was purified by flash column
chromatography (SiO2, Et2O–hexane, 1:10) to give an inseparable
mixture (170 mg) of 16 and 17, and a trace amount of 18. The com-
bined yield of 16 and 17 and the diastereomeric ratio were deter-
1
mined by 400 MHz H NMR spectroscopy to be 93% and 2:98,
respectively.
[a]D20 +97 (c 1.1, CHCl3).
[a]D20 –46.9 (c 0.66, CHCl3).
IR (neat): 2978, 1698, 1455, 1369, 1088 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.30–7.11 (m, 5 H), 4.99 (d,
J = 11.9 Hz, 1 H), 4.22 (d, J = 11.9 Hz, 1 H), 4.17–4.03 (m, 2 H),
3.69 (q, J = 7.3 Hz, 1 H), 3.34, 3.18 (2 s, ratio = 98:2, 3 H), 1.49 (s,
9 H), 1.43 (s, 3 H), 1.33 (d, J = 7.3 Hz, 3 H), 1.22 (t, J = 7.2 Hz, 3
H).
IR (neat): 2977, 1743, 1704, 1455, 1367, 1297, 1175, 1084, 1028
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.34–7.09 (m, 5 H), 4.53, 4.42 (2
d, J = 10.6, 11.2 Hz, ratio = 1:2, 2 H), 4.30–4.11 (m, 3 H), 3.67–
3.47 (m, 1 H), 3.12, 3.06 (2 s, ratio = 1:2, 3 H), 1.44, 1.34 (2 s,
ratio = 1:2, 9 H), 1.40 (t, J = 4.6 Hz, 3 H), 1.30 (d, J = 6.3 Hz, 3 H).
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1376
T. Kawabata et al.
FEATURE ARTICLE
MS (EI): m/z (%) = 365 (M+), 351, 334, 292, 277, 260, 234, 204,
192, 160, 128.
[a]D20 +25 (c 1.0, CHCl3).
IR (neat): 2976, 1728, 1453, 1118 cm–1.
Exact mass calcd for C20H31NO5: 365.2202; found: m/z 365.2198.
1H NMR (400 MHz, CDCl3): d = 7.30–7.16 (m, 5 H), 4.23–4.15,
4.10–4.01 (2 m, ratio = 6:94, 2 H), 3.19 (q, J = 7.3 Hz, 1 H), 1.45
(br s, 2 H), 1.35 (d, J = 7.3 Hz, 3 H), 1.34 (s, 3 H), 1.19 (t, J = 7.3
Hz, 3 H).
MS (EI): m/z (%) = 222 (MH+), 206, 186, 174, 160, 148, 133, 116,
105.
(2S,3S)-N-tert-Butoxycarbonyl-N-methoxymethyl-b-methyl-
phenylalanine Benzyl Ester (22)
Prepared from (2S,3S)-N-tert-butoxycarbonyl-b-methylphenylala-
nine benzyl ester18 according to the procedure for 15 in 78% yield.
[a]D20 –61 (c 1.0, CHCl3).
IR (neat): 2973, 1704, 1455, 1367, 1173, 765 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.40–7.11 (m, 10 H), 5.29–5.08
(m, 2 H), 4.56–4.11 (m, 3 H), 3.71–3.48 (m, 1 H), 3.00, 2.89 (2 s,
ratio = 1:1, 3 H), 1.39, 1.26 (2 s, ratio = 1:1, 9 H), 1.35 (d, J = 6.4
Hz, 3 H).
Exact mass calcd for C13H20NO2 (MH+): 222.1494; found: m/z
222.1500.
A solution of this mixture (75 mg) in 37% aq HCl and 37% aq
HCHO (1:1, 6 mL) was heated under reflux for 3 h. The mixture
was basified with sat. aq Na2CO3 (20 mL) and extracted with EtOAc
(120 mL). The organic layer was washed with brine (20 mL), dried
over anhyd Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography (SiO2, CHCl3–
MeOH, 15:1) to give diastereomerically and analytically pure 27
(29 mg, 35% yield) as a colorless oil.
[a]D20 +4.7 (c 0.7, CHCl3).
IR (neat): 2978, 1726, 1445, 1372, 1200, 1104, 1020 cm–1.
1H NMR (400 MHz, acetone-d6): d = 7.13–6.96 (m, 4 H), 3.99 (q,
J = 7.0 Hz, 2 H), 3.90 (ABq, JAB = 16.0 Hz, DnAB = 39.9 Hz, 2 H),
3.25 (q, J = 7.0 Hz, 1 H), 2.56 (s, 3 H), 1.32 (s, 3 H), 1.18 (d, J = 7.0
Hz, 3 H), 1.06 (t, J = 7.0 Hz, 3 H).
MS (EI): m/z (%) = 413 (M+), 381, 325, 308, 282, 252, 208, 182,
146, 121.
Anal. Calcd for C24H31NO5: C, 69.71; H, 7.56; N, 3.39. Found: C,
69.44; H, 7.59; N, 3.33.
(2R,3S)-N-tert-Butoxycarbonyl-N-methoxymethyl-b-methyl-
phenylalanine Benzyl Ester (24)
Prepared from (2R,3S)-N-tert-butoxycarbonyl-b-methylphenylala-
nine benzyl ester18 according to the procedure for 15 in 80% yield.
[a]D20 +53 (c 0.5, CHCl3).
IR (KBr): 2979, 1737, 1695, 1421, 1366, 1303, 1166, 1085, 1018
MS (EI): m/z (%) = 246 (M – H+), 230, 218, 188, 173, 158, 144.
Exact mass calcd for C15H20NO2 (M – H+): 246.1494; found: m/z
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.33–7.03 (m, 10 H), 4.98–4.41
(m, 5 H), 3.59–3.45 (m, 1 H), 3.31, 3.26 (2 s, ratio = 1:1, 3 H), 1.48
(s, 9 H), 1.25 (d, J = 7.0 Hz, 3 H).
246.1488.
(3S,4R)-3,4-Dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carbox-
ylic Acid Ethyl Ester (28)
MS (EI): m/z (%) = 413 (M+), 381, 325, 308, 282, 252, 208, 182,
146, 121.
Treatment of a 2:98 mixture of 16 and 17 (140 mg) according to the
procedure for 27 gave diastereomerically pure 28 in 71% yield.
[a]D20 –44 (c 0.5, CHCl3).
Anal. Calcd for C24H31NO5: C, 69.71; H, 7.56; N, 3.39. Found: C,
69.49; H, 7.58; N, 3.30.
1H NMR (400 MHz, CDCl3): d = 7.19–7.00 (m, 4 H), 4.26 (q of
ABX, JAB = 13.1 Hz, JAX = 7.3 Hz, DnAB = 5.7 Hz, 2 H), 4.12 (s, 2
H), 2.95 (q, J = 7.0 Hz, 1 H), 2.18 (br s, 1 H), 1.38 (s, 3 H), 1.33 (t,
J = 7.0 Hz, 3 H), 1.15 (d, J = 7.0 Hz, 3 H).
IR (neat): 2976, 1732, 1455, 1373, 1214, 1136 cm–1.
MS (EI): m/z (%) = 233 (M+), 218, 204, 160, 144, 115.
a-Methylation of 22: (2S,3S)-N-tert-Butoxycarbonyl-N-meth-
oxymethyl-a,b-dimethylphenylalanine Benzyl Ester (23)
a-Methylation of 22 (207 mg, 0.50 mmol) was performed according
to the procedure for a-methylation of 15. The residue was purified
by flash column chromatography (SiO2, Et2O–hexane, 1:10) to give
diastereomerically pure 23 (199 mg, 93% yield) as a colorless oil.
[a]D20 +57 (c 1.1, CHCl3).
IR (neat): 2976, 1703, 1455, 1367, 1088 cm–1.
Exact mass calcd for C14H19NO2: 233.1416; found: m/z 233.1407.
1H NMR (400 MHz, CDCl3): d = 7.31–7.15 (m, 10 H), 5.08 (ABq,
JAB = 12.4 Hz, DnAB = 42.3 Hz, 2 H), 4.95 (d, J = 12.8 Hz, 1 H),
4.22 (d, J = 12.8 Hz, 1 H), 3.70 (q, J = 7.3 Hz, 1 H), 3.21 (s, 3 H),
1.46 (s, 3 H), 1.45 (s, 9 H), 1.35 (d, J = 7.3 Hz, 3 H).
MS (EI): m/z (%) = 427 (M+), 396, 382, 352, 340, 322, 308, 296,
282, 266, 222, 208, 190, 176, 160, 146.
References
(1) For recent reviews, see: (a) Corey, E. J.; Guzman-Perez, A.
Angew Chem. Int. Ed. 1998, 37, 388. (b) Christoffers, J.;
Mann, A. Angew. Chem. Int. Ed. 2001, 40, 4591.
(2) Kawabata, T.; Fuji, K. Topics in Stereochemistry, Vol. 23;
Denmark, S. E., Ed.; John Wiley & Sons: New York, 2003,
Chap. 3, 175.
Exact mass calcd for C25H33NO5: 427.2359 (M+); found: m/z
427.2356.
(3) For a recent review on memory of chirality, see: (a) Zhao,
H.; Hsu, D. C.; Carlier, P. R. Synthesis 2005, 1. For
reactions related to memory of chirality, see: (b) Beagley,
B.; Betts, M. J.; Pritchard, R. G.; Schofield, A.; Stoodley, R.
J.; Vohra, S. J. Chem. Soc., Chem. Commun. 1991, 924.
(c) Betts, M. J.; Pritchard, R. G.; Schofield, A.; Stoodley, R.
J.; Vohra, S. J. Chem. Soc., Perkin Trans. 1 1999, 1067.
(d) Gerona-Navarro, G.; Bonache, M. A.; Herranz, R.;
García-López, M. T.; González-Muñiz, R. J. Org. Chem.
2001, 66, 3538. (e) Bonache, M. A.; Gerona-Navarro, G.;
Martín-Martínez, M.; García-López, M. T.; López, P.;
N-Methyl-(3R,4R)-3,4-dimethyl-1,2,3,4-tetrahydroisoquino-
line-3-carboxylic Acid Ethyl Ester (27)
A 94:6 mixture of 16 and 17 (176 mg) was dissolved in 4 M HCl in
EtOAc (3 mL) and the solution was stirred at r.t. for 1 h. The mix-
ture was poured into sat. aq Na2CO3 (20 mL) and extracted with
EtOAc (150 mL). The organic layer was washed with brine (30
mL), dried over anhyd Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by flash column chromatography (SiO2,
CHCl3–MeOH, 20:1) to give a 94:6 mixture of (2R,3R)- and
(2S,3R)-a,b-dimethylphenylalanine ethyl ester as a colorless oil.
Synthesis 2005, No. 8, 1368–1377 © Thieme Stuttgart · New York

FEATURE ARTICLE
a-Alkylation of b-Branched a-Amino Acids via Memory of Chirality
1377
Cativiela, C.; González-Muñiz, R. Synlett 2003, 1007.
(12) Kazmierski, W. M.; Urbanczyk-Lipkowska, Z.; Hruby, V. J.
J. Org. Chem. 1994, 59, 1789.
(13) While N-methylation took place during the transformation
from 16 into 27, it did not during that from 17 into 28,
probably due to the steric hindrance caused by diaxial 3,4-
dimethyl groups in 28.
(f) Carlier, P. R.; Zhao, H.; DeGuzman, J.; Lam, P. C.-H. J.
Am. Chem. Soc. 2003, 125, 11482. (g) Kawabata, T.;
Ozturk, O.; Suzuki, H.; Fuji, K. Synthesis 2003, 505.
(h) Kawabata, T.; Kawakami, S.; Shimada, S.; Fuji, K.
Tetrahedron 2003, 59, 965.
(4) Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew. Chem.
Int. Ed. 2000, 39, 2155.
(5) Kawabata, T.; Kawakami, S.; Majumdar, S. J. Am. Chem.
(14) Monte-Carlo conformational search (5000 steps) and MM3*
calculation were carried out with MacroModel V. 6.0:
Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp,
R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.;
Still, W. C. J. Comp. Chem. 1990, 11, 440.
(15) For utility of non-proteinogenic a-amino acids with
quaternary stereocenters, see: (a) Horwell, D. C.; Hughes,
J.; Hunter, J. C.; Pritchard, M. C.; Richardson, R. S.;
Roberts, E.; Woodruff, G. N. J. Med. Chem. 1991, 34, 404.
(b) Altmann, K.-H.; Altmann, E.; Mutter, M. Helv. Chim.
Acta 1992, 75, 1198. (c) Mendel, D.; Ellman, J.; Schultz, P.
G. J. Am. Chem. Soc. 1993, 115, 4359. (d) Stilz, H. U.;
Jablonka, B.; Just, M.; Knolle, J.; Paulus, E. F.; Zoller, G. J.
Med. Chem. 1996, 39, 2118. (e) Chinchilla, R.; Falvello, L.
R.; Galindo, N.; Nájera, C. Angew. Chem., Int. Ed. Engl.
1997, 36, 995.
(16) For excellent methods for asymmetric synthesis of a,a-
disubtituted a-amino acid derivatives, see: (a) Seebach, D.;
Boes, M.; Naef, R.; Schweizer, W. B. J. Am. Chem. Soc.
1983, 105, 5390. (b) Vedejs, E.; Fields, S. C.; Schrimpf, M.
R. J. Am. Chem. Soc. 1993, 115, 11612. (c) Ferey, V.;
Toupet, L.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int.
Ed. Engl. 1996, 35, 430. (d) Vedejs, E.; Fields, S. C.;
Hayashi, R.; Hitchcock, S. R.; Powell, D. R.; Schrimpf, M.
R. J. Am. Chem. Soc. 1999, 121, 2460. (e) Kuwano, R.; Ito,
Y. J. Am. Chem. Soc. 1999, 121, 3236. (f) Ooi, T.;
Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc.
2000, 122, 5228.
Soc. 2003, 125, 13012.
(6) Kawabata, T.; Chen, J.; Suzuki, H.; Nagae, Y.; Kinoshita, T.;
Chancharunee, S.; Fuji, K. Org. Lett. 2000, 2, 3883.
(7) A similar temperature-dependent decrease in ee was also
observed in the a-methylation of 19: When enolate
formation was performed at –78 °C for 30 min, the
subsequent methylation at –78 °C gave a product of 81% ee.
When enolate formation was performed at –78 °C for 30 min
and then at –40 °C for 30 min, the subsequent methylation at
–78 °C gave a product of 5% ee. Enolate formation at –78 °C
for 30 min and then at 0 °C for 30 min gave a product of 0%
ee. This can be rationalized by temperature-dependent
epimerization of the chiral enolate intermediate J via bond
rotation of the C(2)–N axis. Details are discussed in
reference 2.
(8) Enolate F generated from 7 or 10 is not axially chiral along
the C(2)–N axis because of the same two substituents on the
nitrogen atom, even if the bond rotation is restricted at
–78 °C.
(9) The stereochemistry of 8 and 9 was determined after their
conversion into the corresponding p-nitrobenzamide
derivatives, see ref. 6.
(10) Similar stereochemical results were observed in the
a-allylation of 3 and 6, see reference 6.
(11) Enolate G generated from 11 or 14 is not axially chiral along
the C(2)–N axis because of the same two substituents on the
nitrogen atom, even if the bond rotation is restricted at
–78 °C.
(17) Brown, C. A. J. Org. Chem. 1974, 39, 3913.
(18) Shapiro, G.; Buechler, D.; Marzi, M.; Schmidt, K.; Gometz-
Lor, B. J. Org. Chem. 1995, 60, 4978.
Synthesis 2005, No. 8, 1368–1377 © Thieme Stuttgart · New York