Regio- and stereoselective α-alkylation of N-terminal amino acid residue of peptides using a pyridoxal model compound with a chiral ansa-structure

Article abstract of DOI:10.1016/S0040-4020(01)00512-9

Regio- and stereoselective α-alkylation of N-terminal amino acid residue of peptides was achieved by Li⁺-mediated alkylation of aldimines prepared from the peptides and a pyridoxal model compound having a chiral ansa-structure and an ethoxyetho

Full text of DOI:10.1016/S0040-4020(01)00512-9

TETRAHEDRON
Pergamon
Tetrahedron 57 22001) 5773±5780
Regio- and stereoselective a-alkylation of N-terminal amino acid
residue of peptides using a pyridoxal model compound
with a chiral ansa-structure
Kazuyuki Miyashita, Hiroshi Iwaki, Kuninori Tai, Hidenobu Murafuji, Naoko Sasaki
and Takeshi Imaniship
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
Received 30 March 2001; accepted 9 May 2001
AbstractÐRegio- and stereoselective a-alkylation of N-terminal amino acid residue of peptides was achieved by Li1-mediated alkylation
of aldimines prepared from the peptides and a pyridoxal model compound having a chiral ansa-structure and an ethoxyethoxy group at C-3.
The stereochemistry and stereoselectivity of the reaction were found to be in¯uenced predominantly by the chirality of the model compound
and Li1, but little by the stereochemistry of the original peptides. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
much effort has been paid to the synthesis of unnatural
amino acids.1 In contrast, direct modi®cation of peptides
would be another choice and, in fact, several methods for
this purpose have been reported.2,3 However, most of these
methods deal with the alkylation of peptides at sites other
than the N-terminal position and, consequently, seem to
lack generality. As both liquid- and solid-phase peptide
Peptides containing unnatural amino acid2s) have been
receiving a great deal of attention because of their bio-
chemical and medicinal properties. Such peptides are gener-
ally synthesized by sequential coupling of the respective
amino acids prepared independently. As a consequence,
Figure 1. Unnatural peptide synthesis and structure of pyridoxal derivative Ransa-1.
Keywords: peptide; alkylation; cyclophanes.
Corresponding author. Tel.: 181-6-6879-8200; fax: 181-6-6879-8204; e-mail: imanishi@phs.osaka-u.ac.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020201)00 512-9

5774
K. Miyashita et al. / Tetrahedron 57 *2001) 5773±5780
syntheses are generally achieved by sequential coupling
from a C-terminal amino acid, N-terminal selective modi®-
cation appears to be more useful, particularly when applied
to construction of an unnatural peptide library in the ®eld of
combinatorial chemistry, because it is not necessary to
synthesize the individual unnatural amino acids 2Fig. 1).
O'Donnell and coworkers reported an interesting method
utilizing this idea: direct regioselective a-alkylation of
peptides at the N-terminal position via imine formation,
which appears to be very signi®cant because this modi®-
cation cycle was shown to be incorporated into general
peptide synthesis.3 The only problem with their method is
the lack of stereoselectivity, because they use benzophenone
as an N-terminal activator without any chiral elements
excepting a substrate, peptide. If the a-alkylation takes
place with predictable stereoselectivity, this method would
be more useful and versatile. In previous papers, we
reported asymmetric a-alkylation of a-amino esters using
pyridoxal derivatives which have a chiral ionophore
function and/or a chiral ansa-structure.4 In this paper, we
describe stereoselective and N-terminal selective a-alkyl-
ation of peptides employing our pyridoxal derivative Ransa-1.5
Eventually, it was found that the reaction took place when
DBU was employed 2Table 1, run 1). The reaction rate of 2a
was, as expected, slower than that of the corresponding ester
2b 2run 1 vs. run 2). Interestingly, the stereoselectivity was
found to depend on Li1: R-stereoselectivity was obtained in
the presence of Li1 while S-stereoselectivity was obtained
in the absence of Li1 2run 3).6 The stereoselectivity was
1
determined by the H NMR spectrum of the corresponding
MTPA amide 5a and the stereochemistry was assigned as
shown by comparison of the 1H NMR spectra with those of
the corresponding ester 5b 2Table 2) 2Scheme 1).4
Encouraged by these ®ndings, we studied the benzylation of
dipeptides and a tripeptide 6 made from neutral amino acids
under the conditions described above and the results are
summarized in Table 3. The reactions, as expected,
proceeded at the a-position of the N-terminal amino acid,
regioselectively. Although stereoselectivities observed in
these reactions with or without Li1 were basically the
same as that of the reaction of l-Ala-NHBn 2a, the follow-
ing were observed in the presence of Li1. Changing the
stereochemistry of the C-terminal amino acid from l- to
d-con®guration slightly lowered the stereoselectivity 2run
1 vs. 2 and run 4 vs. 5), but did not reverse the stereoselec-
tivity. It is also noted that the stereoselectivity of the reac-
tion with l-Ala-Gly-NHBn 6b is in the range of those with
l- and d-amino acids at the C-terminal position 2run 3).
However, it is obvious that the bulkiness of the substituent
at the C-terminal amino acid is not related to the stereoselec-
tivity 2run 1 vs. 4 and run 2 vs. 5). The reaction of the
tripeptide 6d also successfully took place with similar
stereoselectivity.
2. Results and discussion
Taking account of application of the N-terminal selective
alkylation not only to liquid-phase synthesis but also to
solid-phase synthesis, we ®rst examined the reaction con-
ditions by employing l-Ala-NHBn 2a in the presence of
3 equiv. of LiClO4 and an organic base. The reaction
with triethylamine, N,N,N0,N0-tetramethylethylenediamine,
4-dimethylaminopyridine or proton sponge did not proceed.
In contrast, stereoselectivities of the reactions in the absence
of Li1 were somewhat lower than those in the presence of
Li1 and were completely reversed as expected. The
tendency of the stereoselectivity such as observed in the
presence of Li1 was not observed 2runs 7±12), which
could be attributable to the fact that the conformation in
the absence of Li1 is not so tightly restricted as that in the
presence of Li1.
Table 1. Alkylation of a-amino ester and amide
Run
2
X
M1
Time 2h)
Product 4
Yield 2%)
R/S
1
2
3
a
b
c
NH
O
NH
LiClO4
LiClO4
None
2
1
4.5
6083:17
72
51
87:13
27:73
Table 2. Chemical shifts 2ppm) for a-CH3 2dH) and CF3 2dF) groups of 5a,b and 15a,b
5a
5b
15a
15b
a-CH3
CF3
1.66 21.72)
269.4 2269.8)
1.67 21.68)
269.5 2269.7)
1.62 21.67)
269.5 2269.8)
1.68 21.70)
269.5 2269.7)
Values in the parentheses are for S-isomers.
Scheme 1.

K. Miyashita et al. / Tetrahedron 57 *2001) 5773±5780
Table 3. Benzylation of peptides 6 in the presence and absence of Li1
5775
Run
Peptide 6
AA
M1
Time 2h)
Benzylated peptide 8
Yield 2%)a
R/S
1
2
3
4
5
6
7
8
a
l-Ala
d-Ala
Gly
l-Val
d-Val
l-Ala-l-Ala
l-Ala
d-Ala
Gly
l-Val
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
None
None
None
None
None
None
4
4
4
4.5
5
5
6
7
7
51
49
46
5088:12
51
48
38
38
36
37
38
37
86:14
74:26
83:17
a0
b
c
c0
d
a
73:27
86:14
24:76
21:79
33:67
20:80
35:65
23:77
a0
b
c
9
10
11
12
7
8
8
c0
d
d-Val
l-Ala-l-Ala
a
Isolated yield based on the peptides 6.
Although slight differences in stereoselectivity between the
peptides examined were observed in the reactions with or
without Li1 as described above, these ®ndings totally show
that the stereochemistry and the size of the substituent at the
C-terminal amino acid do not signi®cantly affect the stereo-
selectivity of the alkylation. In other words, the stereoselec-
tivity of the alkylation predominantly depends on the
chirality of the pyridoxal derivative Ransa-1 and the reaction
condition whether Li1 is employed or not.
Li1 afforded a somewhat lower stereoselectivity than those
with other alkyl bromides, which could be attributable to the
SN20 character of the allylating agent.
The reaction product R-8a, which was shown to be a
mixture of two diastereomers 2R/Sˆ86:14), was treated
with 2R)-MTPACl to give the MTPA amide 15a, which
was also shown to be a mixture of only two diastereomers
in the same ratio by its 1H- and 19F NMR data.7 This result
shows that isomerization at the a-position of the C-terminal
amino ester does not proceed under the conditions of the
a-alkylation. The stereochemistry of the alkylated peptide
8a was established by a sequential peptide coupling method,
as shown in Scheme 2, from optically active amino ester
Alkylation of 6a with other alkyl bromides also took place
under the same conditions as shown in Table 4, giving alkyl-
ated dipeptides 8a and 9±11 with similar stereoselectivity.
Reactions with allyl bromide in the presence and absence of
Table 4. Alkylation of 6a in the presence and absence of Li1
Run
R
M1
Time 2h)
Alkylated peptide
Product
Yield 2%)a
R/S
1
2
3
4
5
6
7
8
Bn±
LiClO4
LiClO4
LiClO4
LiClO4
None
None
None
None
4
4
4.5
4.5
7
7
6
6
8a
9
10
11
8a
9
51
86:14
4-O2NC6H4CH2±
HCuCCH2±
H2CvCHCH2±
Bn±
4-O2NC6H4CH2±
HCuCCH2
H2CvCHCH2±
5085:15
56
48
38
39
84:16
73:24
24:76
24:76
26:74
31:69
10
11
46
42
a
Isolated yield based on the peptide, l-Ala-l-Ala-OBn 6a.

5776
K. Miyashita et al. / Tetrahedron 57 *2001) 5773±5780
We studied the conformation of the aldimine Ransa-7a in the
absence and presence of Li1 to clarify the reaction mecha-
nism. In a previous paper dealing with the a-alkylation of
a-amino esters, we found that the conformation of the imino
ester moiety is restricted in the direction of the C-5 position
in the absence of Li1 to avoid steric repulsion between the
imino ester moiety and the ethoxyethoxy group at C-3,
while the addition of Li1 induces rotation of the C-4±C-40
bond to the direction of the C-3 position to capture Li1
between the imino ester moiety and the ethoxyethoxy
group.8 1H NMR study of Ransa-7a in the absence and
presence of Li1 revealed that this phenomenon takes place
in the case of peptide-aldimine as well 2Fig. 2 and Table 5),
and the C-terminal Ala moiety was shown to be positioned
apart from the reaction center.
Scheme 2.
R-4a prepared according to our previous paper.4 The stereo-
chemistries of the other alkylated peptides 8c±d and 9±11
were assigned by comparison of the H NMR data with
those of R- and S-8a: the chemical shifts for the N-terminal
a-methyl hydrogens of the major isomers 2R-isomers)
obtained in the presence of Li1 always appeared at slightly
lower ®eld than those of minor isomers 2S-isomers) 2see
Section 3). The stereochemistry of 8b was tentatively
assigned as shown by comparison of the 1H- and 19F
NMR spectra of its MTPA amide 15b with those of 5a
and b 2see Table 2 in Section 2).
From the result mentioned above, the stereochemical
outcome observed in the alkylation of the peptides appears
to be attributable to this conformational change induced by
Li1. Taking account of this conformational behavior and the
stereoselectivities observed in the absence and the presence
of Li1, it is obvious that the alkylating agent approaches
from the same side of the ansa-chain in both cases with and
without Li1. The stereoselectivity observed in the presence
of Li1 would be explained by a similar transition state B to
that of a-alkylation of a-amino ester, which we proposed in
a previous paper: the ansa-chain works as a steric barrier to
1
Figure 2. Selected NOE data for Ransa-7a and Ransa-7a-Li1 and conformational change induced by Li1.
Table 5. 1H NMR data for Ransa-7a and Ransa-7a-Li1 measured in CD3CN
Ransa-7a
Ransa-7a-Li1
2-CH2S-
4-CHˆN±
3.59, 4.32 2each 1H, d, Jˆ13.0Hz)
8.85 2s)
3.67, 4.67 2each 1H, d, Jˆ13.0Hz)
3.67, 4.67 2each 1H, d, Jˆ13.0Hz)
8.76 2s)
3.76, 4.34 2each 1H, d, Jˆ13.0Hz)
5-CH2S±
3-side chain H
MeCH2O2CH2)2O±
MeCH2O2CH2)2O±
EtOCH2CH2O±
EtOCH2CH2O±
Ansa-chain H
±SCH2-2CH2)3-CH2S±
±SCH2-2CH2)3-CH2S±
N-terminal Ala
a-Me
1.16 2t, Jˆ7.0Hz)
3.52 2q, Jˆ7.0Hz)
3.68 2m)
1.24 2t, Jˆ7.0Hz)
3.65 2q, Jˆ7.0Hz)
3.67, 3.85 2each 1H, m)
3.97, 4.05 2each 1H, m)
4.04 2m)
2.09±2.18, 2.32±2.250 2each 2H, m)
0.38 21H, m), 0.66±0.92 25H, m)
1.90±2.08, 2.45±2.56 2each 2H, m)
0.39 21H, m), 0.61±0.89 24H, m), 0.96 21H, m)
1.41 2d, Jˆ7.0Hz)
4.01 2q, Jˆ7.0Hz)
1.47 2d, Jˆ7.0Hz)
4.29 2q, Jˆ7.0Hz)
a-H
C-terminal Ala
Amide NH
a-Me
a-H
COOCH2Ph
COOCH2Ph
7.44 2br d, Jˆ7.5 Hz)
1.402d, Jˆ7.5 Hz)
4.51 2qn, Jˆ7.5 Hz)
5.06±5.13 2AB type)
7.30±7.37 2m)
7.702br d, Jˆ7.5 Hz)
1.44 2d, Jˆ7.5 Hz)
4.54 2qn, Jˆ7.5 Hz)
5.12±5.18 2AB type)
7.34±7.40 2m)
Concentration: 0.1 M Ransa-7a in CD3CN; 0.1 M Ransa-7a and 0.5 M LiClO4 in CD3CN.

K. Miyashita et al. / Tetrahedron 57 *2001) 5773±5780
5777
Figure 3. Possible transition states A and B for a-alkylation in the absence and presence of Li1.
the formation of the chelation structure and not to the
approach of the alkylating agent.4b As a consequence, the
si-face appears to be blocked by the chelation structure
formed in another side of the ansa-structure. In contrast,
although the details are still not clear, the reversed stereo-
selectivity observed in the absence of Li1 might be
explained by the fact that the C-terminal amino ester moiety
and/or the ethoxyethoxy group are most likely to occupy the
other side of the ansa-chain to avoid the steric repulsion for
the ansa-chain, which consequently could block the re-face
as illustrated by the transition state A 2Fig. 3).
0.200 mm) was used. Pyridoxal derivative Ransa-1 was
prepared according to our method.4b
3.2. Typical procedure for a-alkylation in the presence
or absence of Li1
Aldimines, 3 and 7, were prepared from Ransa-1 235.5 mg,
0.10 mmol) and amide 2a or peptides 6 20.10 mmol) accord-
ing to the literature procedure8 and were immediately used
1
for the next reaction without puri®cation. Their H NMR
spectra showed that the reaction had proceeded in almost
1
quantitative yield and the aldimines were pure enough. H
In conclusion, we have demonstrated the ®rst example of
N-terminal selective and stereoselective a-alkylation of
peptides. The present reaction has a characteristic feature
in that the stereoselectivity depends on the chirality of the
pyridoxal derivative and the reaction conditions whether
Li1 is employed or not, and not on the stereochemistry of
the peptide, which means that both stereoisomers can be
obtained with predictable stereoselectivity. Although in
this paper we have examined the reaction of the peptides,
which had been made from neutral amino acids, in a liquid-
phase, this method would potentially be of great use for the
synthesis of unnatural peptides, particularly for application
to the construction of an unnatural peptide library.
NMR spectrum for aldimine Ransa-7a is shown in Table 5
and those for Ransa-3a and Ransa-7a0 ±d measured in CDCl3
are as follows: Ransa-3a d: 0.39 21H, m, ansa chain H), 0.66±
0.91 25H, m, ansa chain H), 1.17 23H, t, Jˆ7.5 Hz,
MeCH2O±), 1.53 23H, d, Jˆ7.5 Hz, a-Me), 2.09±2.18,
2.33±2.49 2each 2H, m, ansa chain H), 3.51 22H, q, Jˆ
7.5 Hz, MeCH2O±), 3.57, 4.32 2each 1H, d, Jˆ13.0Hz, 2-
or 5-CH2S), 3.66, 4.702each 1H, d, Jˆ13.5 Hz, 2- or
5-CH2S), 3.67±3.7022H, m, EtOC H2CH2O), 4.00±4.06
22H, m, EtOCH2CH2O), 4.1021H, q, Jˆ7.5 Hz, a-H),
4.32±4.4022H, AB in ABX, Jˆ4.4, 5.1 Hz, NHCH2Ph),
7.16±7.3025H, m, aromatic H), 7.76 21H, br m, amide H),
8.38 21H, s, 6-H), 8.83 21H, s, imine H); Ransa-7a0 d: 0.32
21H, m, ansa chain H), 0.72±0.98 25H, m, ansa chain H),
1.18 23H, t, Jˆ7.0Hz, MeCH2O±), 1.42 23H, d, Jˆ7.0Hz,
N-terminal Ala a-Me), 1.48 23H, d, Jˆ7.0Hz, C-terminal
Ala a-Me), 1.96±2.22, 2.42±2.68 2each 2H, m, ansa chain
H), 3.5022H, q, Jˆ7.0Hz, MeC H2O±), 3.60, 3.62, 4.32,
4.76 2each 1H, d, Jˆ13.0Hz, 2- or 5-CH 2S), 3.61±3.69
22H, m, EtOCH2CH2O), 3.99±4.07 22H, m, EtOCH2CH2O),
4.07 21H, q, Jˆ7.0Hz, N-terminal Ala a-H), 4.68 21H, q,
Jˆ7.0Hz, C-terminal Ala a-H), 5.16±5.22 22H, AB type
CH2Ph), 7.25±7.31 25H, m, aromatic H), 7.58 21H, br d,
Jˆ7.5 Hz, amide H), 8.37 21H, s, 6-H), 8.86 21H, s, imine
H); Ransa-7b d: 0.34 21H, m, ansa chain H), 0.70±0.96 25H,
m, ansa chain H), 1.36 23H, t, Jˆ7.0Hz, MeCH2O±), 1.53
23H, d, Jˆ7.0Hz, Ala a-Me), 1.90±2.18, 2.38±2.66 2each
2H, m, ansa chain H), 3.57 22H, q, Jˆ7.0Hz, MeC H2O±),
3.65, 3.68, 4.33, 4.77 2each 1H, d, Jˆ13.5 Hz, 2- or
5-CH2S), 3.60±3.70 22H, m, EtOC H2CH2O), 4.06±4.13
22H, m, EtOCH2CH2O), 4.08±4.12 22H, AB in ABX, Jˆ
4.8, 5.5 Hz, Gly a-H), 4.14 21H, q, Jˆ7.0Hz, Ala a-H),
5.17 22H, s CH2Ph), 7.26±7.4025H, m, aromatic H), 7.68
3. Experimental
3.1. General
Melting points 2mps) were taken on a Yanagimoto micro-
melting point apparatus and are uncorrected. Infrared
spectra were measured on a JASCO FT/IR-200 Fourier-
transfer infrared spectrometer. 1H NMR spectra were
measured on a JEOL GX-500 2500 MHz) or a Varian
VXR-200 2200 MHz) spectrometer and tetramethylsilane
2TMS) was used as an internal standard. 13C NMR spectra
were measured on a Varian VXR-200 250.3 MHz) with
CDCl3 as an internal standard 277.0ppm). Low and High
resolution mass spectra 2EI-MS and HR-MS) were obtained
by use of a JEOL D-300 mass spectrometer. [a]D values
were obtained on a JASCO DIP-370polarimeter. For silica
gel column chromatography, E. Merck Kieselgel 60 20.063±

5778
K. Miyashita et al. / Tetrahedron 57 *2001) 5773±5780
21H, br m, amide H), 8.38 21H, s, 6-H), 8.89 21H, s, imine
H); Ransa-7c d: 0.40 21H, m, ansa chain H), 0.69±0.96 25H,
m, ansa chain H), 0.89, 0.94 2each 3H, d, Jˆ7.5 Hz, Val
b-Me), 1.25 23H, t, Jˆ7.0Hz, MeCH2O±), 1.34 23H, d,
Jˆ7.0Hz, Ala a-Me), 2.00±2.26, 2.39±2.61 2each 2H, m,
ansa chain H), 2.24 21H, m, Val b-H), 3.57 22H, q, Jˆ
7.0Hz, MeC H2O±), 3.59, 4.36 2each 1H, d, Jˆ13.5 Hz, 2-
or 5-CH2S), 3.64, 4.74 2each 1H, d, Jˆ13.0Hz, 2- or
5-CH2S), 3.63±3.67 22H, m, EtOCH2CH2O), 4.09±4.16
22H, m, EtOCH2CH2O), 4.12 21H, q, Jˆ7.0Hz, Ala a-H),
4.59 21H, dd, Jˆ7.0, 7.5 Hz, Val a-H), 5.09±5.19 22H, AB
type, CH2Ph), 7.18±7.36 25H, m, aromatic H), 7.45 21H, br
d, Jˆ7.0Hz, amide H), 8.4021H, s, 6-H), 8.85 21H, s, imine
H); Ransa-7c0 d: 0.38 21H, m, ansa chain H), 0.65±0.96 25H,
m, ansa chain H), 0.90, 0.94 2each 3H, d, Jˆ7.5 Hz, Val
b-Me), 1.28 23H, t, Jˆ7.0Hz, MeCH2O±), 1.44 23H, d,
Jˆ7.0Hz, Ala a-Me), 2.00±2.21, 2.36±2.59 2each 2H, m,
ansa chain H), 2.22 21H, m, Val b-H), 3.54 22H, q, Jˆ
7.0Hz, MeC H2O±), 3.59, 4.35 2each 1H, d, Jˆ13.5 Hz, 2-
or 5-CH2S), 3.61, 4.79 2each 1H, d, Jˆ13.0Hz, 2- or
5-CH2S), 3.61±3.68 22H, m, EtOCH2CH2O), 4.05±4.12
22H, m, EtOCH2CH2O), 4.16 21H, q, Jˆ7.0Hz, Ala a-H),
4.7021H, dd, Jˆ7.0, 7.5 Hz, Val a-H), 5.14±5.19 22H, AB
type, CH2Ph), 7.15±7.35 25H, m, aromatic H), 7.57 21H, br
d, Jˆ7.0Hz, amide NH), 8.39 21H, s, 6-H), 8.88 21H, s,
imine H); Ransa-7d d: 0.42 21H, m, ansa chain H), 0.65±
0.92 25H, m, ansa chain H), 1.17 23H, t, Jˆ7.5 Hz,
MeCH2O±), 1.38, 1.39, 1.42 2each 3H, d, Jˆ7.0Hz, Ala
a-Me), 1.90±2.15, 2.34±2.49 2each 2H, m, ansa chain H),
3.52 22H, q, Jˆ7.5 Hz, MeCH2O±), 3.59, 3.67, 4.32, 4.68
2each 1H, d, Jˆ13.0Hz, 2- or 5-CH 2S), 3.64±3.72 22H, m,
EtOCH2CH2O), 3.99±4.08 22H, m, EtOCH2CH2O), 4.09,
21H, q, Jˆ7.0Hz, N-terminal Ala a-H), 4.39, 4.55 2each
1H, qn, Jˆ7.0Hz, Ala a-H), 5.08±5.13 22H, AB type
CH2Ph), 6.81, 7.88 2each 1H, br d, Jˆ7.0Hz, amide H),
7.16±7.38 25H, m, aromatic H), 8.35 21H, s, 6-H), 8.86
21H, s, imine H).
were also carried out by the same procedure. Spectral
properties for the alkylated products are shown below.
3.2.1. 2-Amino-2-methyl-3-phenylpropanoyl benzylamide
25
04a). A colorless oil 2Table 1, run 1, R/Sˆ83:17). [a]D
ˆ
119.5 2c 0.51, CHCl3). IR n 2KBr): 3353, 1660, 1506 cm21
.
1H NMR 2270MHz, CDCl 3) d: 1.42 23H, s, a-Me), 1.50
22H, br s, NH2), 2.63 21H, d, Jˆ13.4 Hz, a-CH2Ph), 3.45
21H, d, Jˆ13.4 Hz, a-CH2Ph), 4.33±4.44 22H, AB in ABX,
Jˆ5.5, 6.1 Hz, NHCH2Ph), 7.13±7.27 210H, m, aromatic
H), 7.79 21H, br s, amide NH). 13C NMR 267.8 MHz,
CDCl3) d: 28.1, 43.2, 46.8, 58.4, 126.8, 127.2, 127.6,
128.4, 128.5, 130.4, 137.0, 138.5, 176.2. EI-MS m/z 2%):
269 2M11H, 1.9), 134 2100). High-resolution MS calcd for
C17H20N2O 2M11H): 269.1654, found: 269.1652.
3.2.2. Benzyl 2-amino-2-methyl-3-phenylpropanoate 04b).
Colorless crystals, mp 45±468C 2AcOEt±hexane) 2Table 1,
25
run 2, R/Sˆ87:13). [a]D ˆ125.2 2c 0.51, CHCl3). IR n
2KBr): 3374, 1723, 1593 cm21 1H NMR 2270MHz,
.
CDCl3) d: 1.41 23H, s, a-Me), 1.63 22H, br s, NH2), 2.79±
3.14 22H, AB type, a-CH2Ph), 5.12 22H, s, CO2CH2Ph),
7.02±7.42 210H, m, aromatic H). 13C NMR 267.8 MHz,
CDCl3) d: 26.6, 46.8, 58.8, 66.8, 126.8, 128.3, 128.3,
128.3, 128.5, 129.9, 135.6, 136.4, 176.8. EI-MS m/z 2%):
2702M 11H, 0.1), 91 2100). High-resolution MS calcd for
C17H20NO2 2M11H): 270.1495, found: 270.1495.
3.2.3. 02-Amino-2-methyl-3-phenylpropanoyl)-l-alanine
benzyl ester 08a). A colorless oil 2Table 3, run 1, R/Sˆ
25
86:14). [a]D ˆ135.1 2c 0.50, CHCl3). IR n 2KBr): 3363,
1741, 1668, 1506 cm21 1H NMR 2270MHz, CDCl 3)
.
2R)-isomer d: 1.33 23H, s, N-terminal a-Me), 1.4023H, d,
Jˆ7.3 Hz, C-terminal a-Me), 1.52 22H, br s, NH2), 2.73
21H, d, Jˆ13.5 Hz, a-CH2Ph), 3.25 21H, d, Jˆ13.5 Hz,
a-CH2Ph), 4.57 21H, qn, Jˆ7.3 Hz, a-H), 5.15 22H, s,
CO2CH2Ph), 7.12±7.40210H, m, aromatic H), 7.97 21H,
br s, amide NH). 2S)-isomer d: 1.3023H, d, Jˆ7.3 Hz,
C-terminal a-Me), 1.37 23H, s, N-terminal a-Me), 1.52
22H, br s, NH2), 2.61 21H, d, Jˆ13.5 Hz, a-CH2Ph), 3.36
21H, d, Jˆ13.5 Hz, a-CH2Ph), 4.57 21H, qn, Jˆ7.3 Hz,
a-H), 5.14±5.17 22H, AB type, CO2CH2Ph), 7.12±7.40
210H, m, aromatic H), 7.97 21H, br s, amide NH). High-
resolution MS calcd for C17H20NO2 2M11H): 341.1865,
found: 341.1871.
To a stirred MeCN 21 ml) solution of the aldimine Ransa-3 or
Ransa-7 20.10 mmol), were added LiClO4 232.2 mg,
0.30 mmol) and then DBU 230 ml, 0.20 mmol) under ice-
cooling and the whole was stirred for 5 min at the same
temperature. After addition of benzyl bromide 213.1 ml,
0.11 mmol), the reaction mixture was stirred under ice-
cooling for the period indicated in Tables, then diluted
with ethyl acetate 210ml) and washed with H 2O and satu-
rated NaCl solution. To the organic layer, p-TsOH´H2O
238.6 mg, 0.20 mmol) was added and the whole was stirred
for 30min at room temperature. The reaction mixture was
partitioned with ether and H2O and the ethereal layer was
extracted with H2O. The organic layer was dried, concen-
trated under reduced pressure and puri®ed by silica gel
column chromatography 2ethyl acetate±hexaneˆ1:1) to
give recovered pyridoxal derivative Ransa-1. The aqueous
phase was basi®ed with saturated NaHCO3 solution, satu-
rated with NaCl and extracted with ethyl acetate. The
organic layer was dried and concentrated under reduced
pressure. The resultant residue was puri®ed by silica gel
column chromatography 2ethyl acetate) to give benzylated
product. Diastereomeric mixtures were unseparable under
the conditions. The reaction in the absence of Li1 was
carried out according to the same procedure without the
addition of LiClO4 and alkylations with other alkyl halides
3.2.4.
02-Amino-2-methyl-3-phenylpropanoyl)glycine
benzyl ester 08b). A colorless oil 2Table 3, run 3, R/Sˆ
25
83:17). [a]D ˆ114.5 2c 0.50, CHCl3). IR n 2KBr): 3335,
1
1751, 1629, 1589 cm21. H NMR 2270MHz, CDCl 3) d:
1.37 23H, s, a-Me), 1.46 22H, br s, NH2), 2.69 21H, d, Jˆ
13.4 Hz, a-CH2Ph), 3.32 21H, d, Jˆ13.4 Hz, a-CH2Ph),
3.91±4.15 22H, AB in ABX, Jˆ5.5, 6.1 Hz, Gly a-H),
5.16±5.17 22H, AB type, CO2CH2Ph), 7.23±7.36 210H, m,
aromatic H), 7.98 22H, br s, amide NH). 13C NMR
267.8 MHz, CDCl3) d: 27.7, 41.3, 46.4, 58.3, 67.0, 126.8,
127.6, 128.4, 128.5, 128.6, 130.3, 135.3, 136.8, 169.8,
177.0. EI-MS m/z 2%): 327 2M11H, 0.1), 91 2100). High-
resolution MS calcd for C17H20NO2 2M11H): 327.1708,
found: 327.1697.
3.2.5. 02-Amino-2-methyl-3-phenylpropanoyl)-l-valine
benzyl ester 08c). A colorless oil 2Table 3, run 4, R/Sˆ

K. Miyashita et al. / Tetrahedron 57 *2001) 5773±5780
5779
25
88:12). [a]D ˆ139.2 2c 0.52, CHCl3). IR n 2KBr): 3366,
ABX, Jˆ2.6, 15.9 Hz, CH2CuCH), 4.58 21H, qn, Jˆ
7.1 Hz, a-H), 5.15±5.17 22H, AB type, CO2CH2Ph),
7.12±7.40210H, m, aromatic H), 8.11 21H, br s, amide
NH). 2S)-isomer d: 1.35 23H, s, N-terminal a-Me), 1.43
23H, d, Jˆ7.3 Hz, C-terminal a-Me), 1.52 22H, br s,
NH2), 2.05 21H, t, Jˆ2.6 Hz, CH2CuCH), 2.47±2.75 22H,
AB in ABX, Jˆ2.6, 16.7 Hz, CH2CuCH), 4.58 21H, qn,
Jˆ7.1 Hz, a-H), 5.15±5.17 22H, AB type, CO2CH2Ph),
7.12±7.40210H, m, aromatic H), 8.11 21H, br s, amide
NH). EI-MS m/z 2%): 289 2M11H, 1.1), 91 2100). High-
resolution MS calcd for C17H20NO2 2M11H): 289.1474,
found: 289.1475.
1741, 1671, 1586 cm21 1H NMR 2270MHz, CDCl 3)
.
2R)-isomer d: 0.88, 0.91 2each 3H, d, Jˆ7.0Hz, Val
b-Me), 1.35 23H, s, a-Me), 1.47 22H, br s, NH2), 2.08
21H, m, Val b-H), 2.71 21H, d, Jˆ13.2 Hz, a-CH2Ph),
3.27 21H, d, Jˆ13.2 Hz, a-CH2Ph), 4.53 21H, dd, Jˆ5.0,
7.0Hz, a-H), 5.11±5.2022H, AB type, CO CH2Ph), 7.12±
2
7.38 210H, m, aromatic H), 8.05 21H, br s, amide NH). 2S)-
isomer d: 0.74, 0.75 2each 3H, d, Jˆ7.0Hz, Val b-Me),
1.37 23H, s, a-Me), 1.47 22H, br s, NH2), 2.08 21H, m,
Val b-H), 2.61 21H, d, Jˆ13.2 Hz, a-CH2Ph), 3.41 21H, d,
Jˆ13.2 Hz, a-CH2Ph), 4.46 21H, dd, Jˆ4.9, 7.0Hz, a-H),
5.11±5.2022H, AB type, CO CH2Ph), 7.12±7.38 210H, m,
2
aromatic H), 8.05 21H, br s, amide NH). High-resolution MS
calcd for C17H20NO2 2M11H): 369.1940, found: 369.1949.
3.2.9. [2-Amino-2-methyl-3-pentenoyl]-l-alanine benzyl
ester 011). A colorless oil 2Table 4, run 4, R/Sˆ73:27).
25
[a]D ˆ119.9 2c 0.51, CHCl3). IR n 2KBr): 3310, 1731,
3.2.6. 02-Amino-2-methyl-3-phenylpropanoyl)-l-alanyl-
l-alanine benzyl ester 08d). A colorless oil 2Table 3, run
1653, 1640, 1603 cm21 1H NMR 2270MHz, CDCl 3)
.
2R)-isomer d: 1.33 23H, s, N-terminal a-Me), 1.43 23H, d,
Jˆ7.3 Hz, C-terminal a-Me), 1.57 22H, br s, NH2), 2.09
21H, m, CH2CHvCH2), 2.52 21H, m, CH2CHvCH2),
4.52±4.64 22H, m, CH2CHvCH2), 4.58 21H, qn, Jˆ
7.0Hz, a-H), 5.17±5.22 22H, AB type, CO2CH2Ph),
5.66±5.86 21H, m, CH2CHvCH2), 7.12±7.4021H0 , m,
aromatic H), 8.11 21H, br s, amide NH). 2S)-isomer d:
1.32 23H, s, N-terminal a-Me), 1.42 23H, d, Jˆ7.3 Hz,
C-terminal a-Me), 1.57 22H, br s, NH2), 2.06 21H, m,
CH2CHvCH2), 2.7021H, m, C H2CHvCH2), 4.58 21H,
qn, Jˆ7.0Hz, a-H), 5.04±5.18 22H, m, CH2CHvCH2),
5.17±5.22 22H, AB type, CO2CH2Ph), 5.66±5.86 21H, m,
CH2CHvCH2), 7.12±7.40210H, m, aromatic H), 8.11 21H,
br s, amide NH). EI-MS m/z 2%): 291 2M11H, 2.2), 91
2100). High-resolution MS calcd for C17H20NO2 2M11H):
291.1630, found: 291.1633.
25
6, R/Sˆ86:14). [a]D ˆ129.3 2c 0.50, CHCl3). IR n 2KBr):
3363, 1751, 1672, 1589 cm21. 1H NMR 2270MHz, CDCl 3)
2R)-isomer d: 1.26 23H, s, N-terminal a-Me), 1.35 23H, d,
Jˆ7.3 Hz, a-Me), 1.38 23H, d, Jˆ6.6 Hz, C-terminal
a-Me), 2.72 21H, d, Jˆ13.8 Hz, a-CH2Ph), 3.28 21H, d,
Jˆ13.8 Hz, a-CH2Ph), 4.4021H, qn, Jˆ7.3 Hz, a-H),
4.54 21H, qn, Jˆ6.6 Hz, C-terminal a-H), 5.16±5.18 22H,
AB type, CO2CH2Ph), 6.76 21H, br s, amide NH), 7.14±7.39
210H, m, aromatic H), 7.81 21H, br s, amide NH). 2S)-isomer
d: 1.22 23H, d, Jˆ6.6 Hz, C-terminal a-Me), 1.38 23H, s,
N-terminal a-Me), 1.41 23H, d, Jˆ7.3 Hz, a-Me), 2.64
21H, d, Jˆ13.8 Hz, a-CH2Ph), 3.35 21H, d, Jˆ13.8 Hz,
a-CH2Ph), 4.4021H, qn, Jˆ7.3 Hz, a-H), 4.54 21H, qn,
Jˆ6.6 Hz, C-terminal a-H), 5.16±5.18 22H, AB type,
CO2CH2Ph), 6.78 21H, br s, amide NH), 7.14±7.39 210H,
m, aromatic H), 7.81 21H, br s, amide NH). EI-MS m/z 2%):
412 2M11H, 1.5), 91 2100). High-resolution MS calcd for
C17H20NO2 2M11H): 412.2158, found: 412.2155.
3.2.10. Benzyl 0R)-2-0tert-Butoxycarbonylamino)-2-methyl-
3-phenylpropanoate 012). To a stirred solution of the
dialkyl amino ester R-4a 230.2 mg, 0.11 mmol) in dioxane
21 ml) were added triethylamine 234.2 ml, 0.11 mmol) and
di-tert-butyl dicarbonate 248.8 mg, 0.22 mmol) and the
whole mixture was stirred for 6 h at room temperature.
The reaction mixture was diluted with ethyl acetate and
washed with saturated NaCl solution, dried over Na2SO4,
and concentrated under reduced pressure. The resultant
residue was puri®ed by silica gel column chromatography
2ethyl acetate±hexane, 1:2) to give 12 240.6 mg, 98%) as
3.2.7. [2-Amino-2-methyl-3-04-nitrophenyl)propanoyl]-
l-alanine benzyl ester 09). A colorless oil 2Table 4, run
25
2, R/Sˆ85:15). [a]D ˆ130.5 2c 0.51, CHCl3). IR n
1
2KBr): 3323, 1722, 1672, 1516 cm21. H NMR 2270MHz,
CDCl3) 2R)-isomer d: 1.4023H, s, N-terminal a-Me), 1.41
23H, d, Jˆ6.8 Hz, C-terminal a-Me), 1.62 22H, br s, NH2),
2.74 21H, d, Jˆ13.1 Hz, a-CH2Ph), 3.48 21H, d, Jˆ13.1 Hz,
a-CH2Ph), 4.53 21H, qn, Jˆ6.8 Hz, a-H), 5.22±5.39 22H,
AB type, CO2CH2Ph), 7.12±7.40210H, m, aromatic H),
7.97 21H, br s, amide NH). 2S)-isomer d: 1.29 23H, d,
Jˆ6.8 Hz, C-terminal a-Me), 1.43 23H, s, N-terminal
a-Me), 1.62 22H, br s, NH2), 2.7021H, d, Jˆ13.1 Hz, a-
CH2Ph), 3.53 21H, d, Jˆ13.1 Hz, a-CH2Ph), 4.53 21H, qn,
Jˆ6.8 Hz, a-H), 5.22±5.39 22H, AB type, CO2CH2Ph),
7.12±7.40210H, m, aromatic H), 7.97 21H, br s, amide
NH). EI-MS m/z 2%): 386 2M11H, 0.9), 91 2100). High-
resolution MS calcd for C17H20NO2 2M11H): 386.1638,
found: 386.1636.
25
colorless crystals, mp 89±908C. [a]D ˆ111.5 2c 0.92,
1
CHCl3). IR n 2KBr): 3428, 1714, 1496 cm21. H NMR
2270MHz, CDCl 3) d: 1.44 29H, s, t-Bu), 1.58 23H, s,
a-Me), 3.19±3.38 22H, AB type, a-CH2Ph), 5.08 21H, br
s, NH), 5.16 22H, s, CO2CH2Ph), 6.99±7.36 210H, m,
aromatic H). 13C NMR 267.8 MHz, CDCl3) d: 23.7, 28.4,
41.6, 60.2, 67.3, 126.8, 128.1, 128.4, 128.5, 130.1, 135.4,
136.3, 154.3, 173.8. EI-MS m/z 2%): 369 2M11H, 2.3), 178
2100). High-resolution MS calcd for C22H27NO4 2M11H):
369.1940, found: 369.1949.
3.2.8. [2-Amino-2-methyl-3-pentynoyl]-l-alanine benzyl
ester 010). A colorless oil 2Table 4, run 3, R/Sˆ84:16).
3.2.11.
0R)-2-0tert-Butoxycarbonylamino)-2-methyl-3-
phenylpropanoic acid 013). A mixture of 12 240.6 mg,
0.11 mmol) and 10% Pd±C 250 mg) in ethyl acetate 21 ml)
was stirred under atmospheric pressure of H2 for 4 h at room
temperature. After being ®ltered, the reaction mixture was
concentrated and the residue was puri®ed by aluminum
oxide column chromatography 2ethyl acetate±MeOH,
25
[a]D ˆ126.1 2c 0.51, CHCl3). IR n 2KBr): 3292, 2119,
1733, 1666, 1588 cm21 1H NMR 2270MHz, CDCl 3)
.
2R)-isomer d: 1.36 23H, s, N-terminal a-Me), 1.43 23H, d,
Jˆ7.3 Hz, C-terminal a-Me), 1.52 22H, br s, NH2), 2.03
21H, t, Jˆ2.6 Hz, CH2CuCH), 2.50±2.66 22H, AB in

5780
K. Miyashita et al. / Tetrahedron 57 *2001) 5773±5780
10:1) to give 13 230.6 mg, quant.) as colorless crystals, mp
0.012 mmol) and the whole was stirred at room temperature
for 2 h. After being diluted with ethyl acetate, the reaction
mixture was washed successively with saturated NaHCO3
solution, 5% HCl, water and brine, dried over Na2SO4 and
concentrated under reduced pressure to give the amide 5a,b
or 15a,b in almost quantitative yield. The optical purities of
these compounds were obtained by 1H- and 19F NMR
analyses.
24
158±1608C 2ethyl acetate). [a]D ˆ26.16 2c 1.72, CHCl3).
1
IR n 2KBr): 3421, 1713, 1453 cm21. H NMR 2270MHz,
CDCl3) d: 1.48 29H, s, t-Bu), 1.53 23H, s, a-Me), 3.25±3.32
22H, AB type, a-CH2Ph), 4.99 21H, br s, NH), 7.13±7.31
25H, m, aromatic H). 13C NMR 267.8 MHz, CDCl3) d: 23.5,
28.4, 41.3, 60.0, 127.0, 128.2, 130.3, 136.0, 154.8, 179.0.
EI-MS m/z 2%): 279 2M11H, 5.7). High-resolution MS
calcd for C15H21NO4 2M11H): 279.1470, found: 279.1467.
Acknowledgements
3.2.12. [0R)-2-0tert-Butoxycarbonylamino)-2-methyl-3-
phenylpropanoyl]-l-alanine benzyl ester 014). To a
stirred solution of 13 230.6 mg, 0.11 mmol) and HOBt
229.6 mg, 0.22 mmol) in ethyl acetate 21 ml) were added
DCC 244.8 mg, 0.22 mmol) and l-Ala-OBn 239.0mg,
0.22 mmol) and the whole was stirred for 24 h at room
temperature. After being ®ltered, the reaction mixture was
successively washed with 5% HCl, saturated NaHCO3
solution, water, and saturated NaCl solution, dried over
Na2SO4 and concentrated under reduced pressure. The
resultant residue was puri®ed by silica gel column chroma-
tography 2ethyl acetate±hexane, 1:2) to give 14 as colorless
This work was supported by SUNBOR Grant and also by
Grant-in-Aid for Scienti®c Research 2C) No. 09672282 and
2B) 11470469 from Japan Society for Promotion of Science.
References
1. Williams, R. M. Synthesis of Optically Active a-Amino Acids,
Pergamon: Oxford, 1989. Heimgartner, H. Angew. Chem., Int.
Ed. Engl. 1991, 30, 238. Wirth, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 225.
24
crystals, mp 84±858C 2ethyl acetate±hexane). [a]D ˆ42.1
2. Polt, R.; Seebach, D. J. Am. Chem. Soc. 1989, 111, 2622.
Miller, S. A.; Grif®ths, S. L.; Seebach, D. Helv. Chim. Acta
1993, 76, 563. Seebach, D.; Beck, A. K.; Bossler, H. G.; Gerber,
C.; Ko, S. Y.; Murtiashaw, C. W.; Naef, R.; Shoda, S.; Thaler,
A.; Krieger, M.; Wenger, R. Helv. Chim. Acta 1993, 76, 1564.
Bossler, H. G.; Seebach, D. Helv. Chim. Acta 1994, 77, 1124.
Bossler, H. G.; Waldmeier, P.; Seebach, D. Angew. Chem., Int.
Ed. Engl. 1994, 33, 439. Kazmaier, U. J. Org. Chem. 1994, 59,
6667.
2c 0.71, CHCl3). IR n 2KBr): 3320, 1716, 1669, 1496 cm21
1H NMR 2270MHz, CDCl 3) d: 1.41 23H, d, Jˆ7.0Hz,
.
C-terminal a-Me), 1.45 29H, s, t-Bu), 1.56 23H, s, N-term-
inal a-Me), 3.08±3.33 22H, AB type, a-CH2Ph), 4.62 21H,
qn, Jˆ7.0Hz, a-H), 4.81 21H, br s, NH), 5.17 22H, s,
CO2CH2Ph), 6.91 21H, br d, Jˆ7.0Hz, NH), 7.11±7.35
210H, m, aromatic H). 13C NMR 267.8 MHz, CDCl3) d:
18.4, 23.6, 28.3, 41.6, 48.3, 59.8, 67.1, 80.2, 126.9, 128.1,
128.2, 128.4, 128.6, 130.5, 135.3, 136.0, 154.5, 172.7,
173.4. EI-MS m/z 2%): 4402M 1, 1.2), 349 2M12Bn, 25).
High-resolution MS calcd for C25H32N2O5 2M1): 440.2311,
found: 440.2300.
3. O'Donnell, M. J.; Zhou, C.; Scott, W. L. J. Am. Chem. Soc.
1996, 118, 6070. Scott, W. L.; Zhou, C.; Fang, Z.; O'Donnell,
M. J. Tetrahedron Lett. 1997, 38, 3695.
4. 2a) Miyashita, K.; Miyabe, H.; Tai, K.; Kurozumi, C.; Imanishi,
T. Chem. Commun. 1996, 1073. Miyashita, K.; Miyabe, H.; Tai,
K.; Kurozumi, C.; Iwaki, H.; Imanishi, T. Tetrahedron 1999,
55, 12109. 2b) Miyashita, K.; Miyabe, H.; Tai, K.; Iwaki, H.;
Imanishi, T. Tetrahedron 2000, 56, 4691.
3.2.13. [0R)-2-Amino-2-methyl-3-phenylpropanoyl]-l-ala-
nine benzyl ester 0R-8a). To a stirred solution of 14
239.9 mg, 0.091 mmol) in CH2Cl2 20.5 ml) was added
tri¯uoroacetic acid 20.5 ml) under ice-cooling and the
whole mixture was stirred for 3 h at the same temperature.
After concentration under reduced pressure, the residue was
dissolved in ethyl acetate and saturated NaHCO3 solution.
The organic phase was separated and the aqueous phase was
extracted three times with ethyl acetate. The combined
organic layer was washed with water and saturated NaCl
solution, dried over Na2SO4 and concentrated under reduced
pressure. The resultant residue was puri®ed by silica gel
column chromatography to give R-8a 227.9 mg, 90%) as a
5. A part of this work appeared in a preliminarily communication:
Miyashita, K.; Iwaki, H.; Tai, K.; Murafuji, H.; Imanishi, T.
Chem. Commun. 1998, 1987.
6. The stereoselectivity of the reaction in the presence of 5 equiv.
of LiClO4 was the almost same as that in the presence of
3 equiv. of LiClO4.
7. The 1H and 19F NMR spectra of 15a showed a pair of signals in
a ratio of 86:14 at dH 1.62 and 1.67 2N-terminal a-CH3) and at
dF 269.5 and 269.8, respectively. The corresponding MTPA
amide obtained starting from l-Ala-dl-Ala-OBn by the same
reaction procedures was shown to be a mixture of four isomers
by the same spectra: dH 1.60, 1.62, 1.66, 1.67 2N-terminal
a-CH3) and dF 269.8, 269.5, 269.5, 269.4. This result
shows that the pair of signals observed in the spectra of 15a
was due to a diastereomeric mixture, not due to a mixture of
geometrical isomers of an amide bond, and, at the same time,
that no racemization is involved in the alkylation procedure.
8. Miyashita, K.; Miyabe, H.; Kurozumi, C.; Tai, K.; Imanishi, T.
Tetrahedron 1996, 52, 12125.
colorless oil, [a]D ˆ141.6 2c 0.55, CHCl3). 1H NMR spec-
24
trum was identical with that of the major compound
obtained by the direct benzylation of l-Ala-l-Ala-OBn.
3.3. Preparation of MTPA amide
To
a solution of amino compound 4a,b or 8a,b
20.010 mmol) in dry pyridine 20.1 ml) containing a catalytic
amount of DMAP was added 2R)-MTPACl 22.2 ml,