Diastereoselective synthesis of β-amino acid derivatives from dihydropyridones

Article abstract of DOI:10.1016/j.tet.2008.05.073

A new method for the diastereoselective preparation of stereoisomeric 2,3-disubstituted β-amino acids is presented. It is based on trans- and cis-2,3-disubstituted dihydropyridones, which were derived from 2-monosubstituted N-acyl dihydropyridone derivatives. Alkylation of the enolates of 2-substituted dihydropyridones gave trans-2,3-disubstituted dihydropyridones with high diastereoselectivities. Inversion of the stereocenter at C-3 of the dihydropyridone nucleus by a deprotonation/reprotonation sequence yielded the stereoisomeric cis-2,3-disubstituted dihydropyridones in high yields and diastereoselectivities. Following removal of the N-acyl protective group, oxidative degradation of the resulting cis- or trans-2,3-disusbtituted dihydropyridones, respectively, by sodium periodate led to the corresponding diastereomeric β-amino acids.

Full text of DOI:10.1016/j.tet.2008.05.073

Tetrahedron 64 (2008) 7273–7282
Contents lists available at ScienceDirect
Tetrahedron
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Diastereoselective synthesis of b-amino acid derivatives from dihydropyridones
,
Markus Ege a, Klaus T. Wanner b
*
a Wacker Chemie AG, Hanns-Seidel-Platz 4, 81737 Mu¨nchen, Germany
b Department of PharmacydCenter for Drug Research, Ludwig-Maximilians-Universita¨t Mu¨nchen, Butenandtstrasse 7, Haus C, 81377 Mu¨nchen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 April 2008
Received in revised form 9 May 2008
Accepted 15 May 2008
Available online 21 May 2008
A new method for the diastereoselective preparation of stereoisomeric 2,3-disubstituted b-amino acids is
presented. It is based on trans- and cis-2,3-disubstituted dihydropyridones, which were derived from 2-
monosubstituted N-acyl dihydropyridone derivatives. Alkylation of the enolates of 2-substituted dihy-
dropyridones gave trans-2,3-disubstituted dihydropyridones with high diastereoselectivities. Inversion
of the stereocenter at C-3 of the dihydropyridone nucleus by a deprotonation/reprotonation sequence
yielded the stereoisomeric cis-2,3-disubstituted dihydropyridones in high yields and diaster-
eoselectivities. Following removal of the N-acyl protective group, oxidative degradation of the resulting
cis- or trans-2,3-disusbtituted dihydropyridones, respectively, by sodium periodate led to the corre-
To the memory of A. I. Meyers
Keywords:
sponding diastereomeric b-amino acids.
b
-Amino acids
Ó 2008 Elsevier Ltd. All rights reserved.
Stereoselective enolate alkylation
Dihydropyridones
Stereoinversion
Oxidative ring cleavage
1. Introduction
derivatives substituted in the 3-position and optionally also at the
amino group (Scheme 1).4 In this synthetic concept, the dihy-
b
-Amino acid derivatives are important structural motifs in
natural products and pharmacologically active compounds.1 An
easy and general access to -amino acid derivatives with arbitrary
dropyridone skeleton 1 serves as a masked b-alanine equivalent.
For the successful implementation of this concept it was essential
to find a suitable method effecting ring cleavage and the extrusion
of the two unsaturated carbon atoms present in the starting com-
b
substitution pattern is therefore an important issue. As part of our
research program aimed at the development of GABA uptake in-
pound resulting in the formation of the b-alanine skeleton. In the
hibitors2 we focused on
b
-amino acid derivatives as potentially
treatment of the respective starting material with sodium period-
ate and subsequently with sodium hydroxide we found a procedure
well suited for this purpose. So far this method has been applied to
bioactive compounds. For a systematic examination of the struc-
ture–activity relationship a general method was required, which
allows the synthesis of
substituents at the 2- and 3-positions as well as at the
b
-amino acid derivatives with various
-amino
the synthesis of b-alanine derivatives provided with substituents
b
only in the 3-position, or in the 3-position and at the amino group,
like 3 and 4, employing dihydropyridones 1 and 2 as starting
compounds (Scheme 1).4
group. In the drug development process it is also crucial to possess
a general and preferably stereoselective method giving access to all
diastereomers of pharmacologically active agents. This is necessary
as ligand target interactions are in general highly stereospecific
events. Thus, a highly flexible yet diastereoselective method for the
R1
N
R1
1) NaIO4
2) NaOH
83-95%
3 2
R3
O
R3
N
H
COOH
synthesis of a,b-disubstituted b-amino acids was needed.
In recent reviews, a number of methods for the synthesis of b-
amino acid derivatives were described.3 But, as several authors
pointed out,3b there is still a need for more efficient methods for the
R1= Me, Ph or
-CH=CH2
3
1 (R3 = H)
)
3 (R = H
4 (R3 = Me)
2 (R3 = Me)
diversity oriented synthesis of
published a new method for the preparation of
b-amino acids. We have recently
Scheme 1.
b-amino acid
As indicated in Scheme 2,
b
-amino acids with any arbitrary
substitution pattern might be derived from dihydropyridones
provided the latter are available in the appropriately substituted
* Corresponding author. Tel.: þ49 89 2180 77249; fax: þ49 89 2180 77247.
E-mail address: klaus.wanner@cup.uni-muenchen.de (K.T. Wanner).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.073

7274
M. Ege, K.T. Wanner / Tetrahedron 64 (2008) 7273–7282
form. In addition the relative, possibly even the absolute stereo-
chemistry should be controllable if appropriate measures are taken
for the synthesis of substituted dihydropyridones. When turned
into the final compounds these must reflect the stereochemistry of
the starting materials as long as no isomerization takes place. In
this article, we wish to report the successful expansion of the
dihydropyridones have been published to date we expected that
substantial investigations would be necessary, especially as dia-
stereoselective epimerization reactions of
a,b-disubstituted ke-
tones are known to be highly dependent on the reaction conditions
and the structural properties of the enolates employed.6
In the final step, the diastereomeric pure dihydropyridones 9
concept described above to the synthesis of 2,3-disusbtituted
amino acids in a diastereoselective approach.
b
-
and 10 should be converted to the corresponding b-amino acid
derivatives 6 and 7 employing the NaIO4 ring cleavage procedure4
that had proven its worth for the aforementioned synthesis of 3-
substituted
special interest whether these transformations occur without epi-
merization in the -position of the carbonyl group of 9 or 10. If this
stereocenter remained unaffected it would be very advantageous
b-amino acids (Schemes 1 and 2, 3 and 4). It was of
R1
R1
R2
a
COOH
H2N
COOH
COOH
H2N
for the scope and value of this diversity oriented
synthesis.
b-amino acid
6
3
2
3
HN
O
2. Results and discussion
R1
5
R1
R2
The starting compounds 8a and 8b were synthesized as de-
scribed in literature by treating 4-methoxypyridine with benzoyl
chloride and TMSOTf and by subsequently trapping the resulting N-
acyliminium ion with Grignard reagents (Scheme 4).4 Of course,
these addition reactions could also have been performed in an
asymmetric manner by substituting the N-benzoyl group with
a chiral auxiliary to provide the 2-substituted dihydropyridones in
enantiopure form.7 No asymmetric methods were employed,
however, as the main goal of this study was to demonstrate that the
Me
N
H
COOH
H2N
7
4
Scheme 2.
As a prerequisite for the synthesis of the desired 2,3-dis-
ubstiuted -amino acids an efficient and diastereoselective access
b
to the respective dihydropyridones was needed. The diaster-
eoselective alkylation of the 2-subtituted N-benzoyldihydropyr-
idones seemed best suited to achieve this as the alkylation
reactions of the enolate of 8 should allow the diastereoselective
introduction of substituents in the 3-position (see Scheme 3). The
compounds 8 were available to us as they had been used as pre-
concept of utilizing dihydropyridone derivatives in
synthesis can also be applied to the preparation of 2,3-di-
substituted -amino acids. Accordingly, all compounds described
b-amino acid
b
here are racemic mixtures.
cursors for the preparation of the monosubstituted b-amino acids
3.4 However, regarding the substitution of the 3-position so far only
methyl groups had been introduced by alkylation of the enolates of
the respective dihydropyridones using methyl iodide furnishing the
corresponding trans-2,3-disubstituted dihydropyridones 9.5a Now,
we wanted to find out whether the known reaction conditions
could also be applied to alkylation reactions with other alkyl ha-
lides. Furthermore, the cis-2,3-disubstituted dihydropyridones 10
were thought to become available from the trans-substituted de-
rivatives 9 by deprotonation of C-3 of the latter and subsequent
diastereoselective reprotonation of the enolate generated this way.
As no attempts for diastereoselective epimerisation reactions of
O
Cl
R1
N
Ph
O
1) TMSOTf
2) R1MgBr
3) 2 M HCl
O
+
Ph
N
OMe
8a: R1 = Me: 85 %
8b: R1 = Ph: 88 %
Scheme 4.
Initial experiments for the alkylation of 8a and 8b via their
enolates were performed following literature procedure
a
employing methyl iodide as electrophile that had been proven to be
successful in methylation reactions of related systems5a,8 (Table 1).
When the reaction was performed that way, i.e., the starting
material was treated with LiHMDS at ꢀ78 ꢁC followed by methyl
iodide, and the mixture was subsequently allowed to warm to rt, in
both cases, using the dihydropyridones 8a and 8b the methylated
products 9a and 9c, respectively, were obtained in very high yields
and in diastereomeric pure form (Table 1, entries 1 and 4), as in-
dicated by 1H NMR spectra. However, the analogously performed
syntheses of 9b and 9d using benzyl bromide as alkylating agent
gave less satisfying results (Table 1, entries 2 and 5). Even though 9b
was obtained in diastereomeric pure form it was accompanied by
the dibenzylation product 11 (Fig. 1) that had formed in a yield of
10% (Table 1, entry 2 and Fig. 1). In the case of 9d, the situation was
even worse as a mixture of the desired trans-derivative and its
cis-diastereomer formed (Table 1, entry 5). In the course of the
subsequently performed optimization of the benzylation reactions
of 8a and 8b some quench experiments with D2O were also carried
out. These indicated that even when applied in excess LiHMDS is
not capable of deprotonating the once 3-alkylated dihydropyr-
idones, i.e., 9, as long as the temperature is kept at ꢀ78 ꢁC. This
changed, however, when the temperature was raised. Accordingly,
the undesired side reactions, such as epimerization and
R1
N
R1
O
2 3
O
H2N
COOH
Ph
8
3
R2
R1
N
R1
R2
O
H2N
COOH
O
O
Ph
9
6
R1
N
R2
R1
R2
O
H2N
COOH
Ph
10
7
Scheme 3.

M. Ege, K.T. Wanner / Tetrahedron 64 (2008) 7273–7282
7275
Table 1
Table 2
Diastereoselective synthesis of trans-2,3-disubstituted dihydropyridones 9
Diastereoselective epimerisation of the trans-2,3-methyl-dihydropyridone 9a
employing LDA as base
R1
N
R2
R1
N
R2
1) 1.15 equiv LiHMDS,
THF, 1 h, -78 °C
2) 3 equiv R2X, t, T
Me
N
Me
Me
N
Me
O
O
1) 2.0 equiv LDA,
O
O
O
O
12 min, -78 °C, THF
2 3
O
N
O
2 3
+
O
O
Ph
Ph
Ph
2) 1 h, rt
Ph
Ph
8
9
10
3) H+ -source, -78 °C
10a
9a
R1
R2
X
t (h)
T
Product
Entry
Hþ-source
Yieldd [%]
dra (10a/9a)
Entry
8
1
2
Ethyl salicylateb
2 M HClc
82
83
>99:1
99:1
9
Yield (%)
dra (9/10)
1
2
3
4
5
6
a
a
a
b
b
b
Me
Me
Me
Ph
Ph
Ph
Me
Bn
Bn
Me
Bn
Bn
I
Br
I
I
Br
I
2
1.25
29
3
2
24
ꢀ78 ꢁC/rt
ꢀ78 ꢁC/rt
a
b
b
c
d
d
91
81b
96
90
91
92
>99:1
>99:1
>99:1
>99:1
94:6
Determined via 1H NMR spectra.
a
The enolate of 9a was added to a precooled solution (ꢀ78 ꢁC) of the Hþ-source in
b
ꢀ78 ꢁ
C
ꢀ78 ꢁC/rt
ꢀ78 ꢁC/rt
THF.
Addition of the Hþ-source to the solution of the enolate of 9a at ꢀ78 ꢁC.
c
d
ꢀ78 ꢁ
C
>99:1
The yield refers to both diastereomers, if a mixture of diastereomers was
obtained.
Assigned from 1H NMR spectra.
a
b
Compound 11 (Fig. 1) was isolated with a yield of 10%.
different and therefore a method that is suitable for these sub-
strates, 9a and 9d, should work in almost all other cases as well.
Unfortunately, the quantitative deprotonation of 9a, an in-
dispensable prerequisite for the intended stereoinversion, proved
to be difficult. Of the various bases that were tried out LDA
appeared to be best suited. It was, however, crucial to add the ke-
tone 9a slowly to LDA, and to apply a significant excess of LDA (in
total 2.0 equiv of LDA, Table 2), as otherwise 9a underwent a rapid
and extensive decomposition that could easily be spotted by the
discoloration of the reaction mixture. For the reprotonation of the
enolate of 9a ethyl salicylate was applied, which is common for
diastereoselective epimerization reactions of cyclic ketones having
Bn
Me
N
Bn
O
O
Ph
11
Figure 1. Over-alkylation product 11.
over-alkylation, must take place during the warm up of the reaction
mixture. Consequently we examined whether it was necessary to
raise the temperature from ꢀ78 ꢁC to a higher temperature to ac-
complish the alkylation reaction or whether it could be affected
even at ꢀ78 ꢁC. With benzyl bromide no alkylation of the enolate of
8a occurred at ꢀ78 ꢁC or at ꢀ60 ꢁC for instance. However, with the
more reactive benzyl iodide the enolates of 8a and 8b underwent
a smooth reaction at ꢀ78 ꢁC which, to our delight, then provided
the trans-2,3-disubstituted dihydropyridones 9b and 9d in high
yields and without the formation of the side products observed
before resulting from epimerization (cis-dihydropyridone) or over-
alkylation (11) (Table 1, entries 3 and 6). As a consequence, all the
dihydropyridones 9 were accessible with high diastereoselectivities
and in high yields (Table 1, entries 1, 3, 4, and 6).
The high diastereoselectivity observed in the alkylation re-
actions of the dihydropyridones 8 is easily explained by the
geometry of their enolates (Scheme 5). As doubly unsaturated pi-
peridine derivatives, the enolates of 8 must be almost planar.5 As
a result of the A(1,3) strain arising from the benzamide moiety R1 is
forced into a pseudo axial position. With the ‘upper’ face being
shielded, the electrophile will enter the molecule from the oppo-
site, less hindered side that is also favored for stereoelectronic
reasons and leads to the trans-configuration found in product 9.
small substituents in the a- and b
-position of the carbonyl group.6
Under these conditions, the inversion reaction proceeded with high
diastereoselectivity providing the cis-2,3-disubstituted dihy-
dropyridone 10a in a high yield and diastereomerically pure form
(Table 2, entry 1). A further experiment with aqueous hydrogen
chloride revealed that this reagent produces a very high diaster-
eoselectivity in the reprotonation step of the enolate of 9a as well
(Table 2, entry 2). This shows that nature and structural properties
of the proton source do not have a significant influence on the
diastereoselectivity of the reprotonation process of the enolate of
9a. But obviously the use of hydrochloric acid has a clear advantage
over that of ethyl salicylate, as no additional organic compound is
introduced in the reaction mixture that needs to be separated from
the final product.
When applied to 9d, the results of the reaction conditions op-
timized for a stereoinversion of 9a were utterly disappointing. The
reaction only led to a mixture of a vast number of unidentified
products. After extensive experimentation, we were very pleased to
discover that this problem could be solved by using LiHMDS as
base. As mentioned above, LiHMDS does not deprotonate dihy-
dropyridones such as 9d at ꢀ78 ꢁC. However, we found that a clean
deprotonation can be effected when this step is performed at
higher temperatures, i.e., at rt. After treatment of 9d with 2.0 equiv
of LiHMDS at rt (3 h at total) and subsequent reprotonation reaction
by addition of the enolate to a precooled solution (ꢀ78 ꢁC) of ethyl
salicylate the cis-isomer 10b was obtained in a large excess over the
trans-isomer (92:8, 80% combined yield, Table 3, entry 3). The yield
and diastereoselectivity were even improved (94:6, 83% combined
yield, Table 3, entry 4) when the solution of ethyl salicylate was
added to the precooled solution of the analogously generated
enolate of 9d. Interestingly, the cis-2,3-dihydropyridone 10b was
formed with a still higher diastereoselectivity when hydrochloric
acid was used instead of ethyl salicylate as the proton source (97:3,
Table 3, entry 5).
R1
R1
H
H
O
O
Ph
O
N
O
N
H
R2Hal
Ph
H
R2
enolate of 8
9
Scheme 5.
As this study was aimed at the diastereoselective preparation of
the different diastereomers of the final amino acids the cis-2,3-
disubstituted dihydropyridones were required as well. A diaster-
eoselective epimerisation of the trans-2,3-disubstituted dihy-
dropyridones 9 (Table 2) by deprotonation of 9 at 3-position and
subsequent diastereoselective reprotonation with inversion of the
stereoconfiguration was considered the most promising method. To
optimize the reaction conditions, the dihydropyridones 9a and 9d
were selected. The steric demand of their substituents is quite
Fortunately, the new method based on LiHMDS proved suitable
for the diastereoselective epimerization of 9a, as well. When

7276
M. Ege, K.T. Wanner / Tetrahedron 64 (2008) 7273–7282
Table 3
mixture, initiates side reactions leading to the decomposition of 9d.
In the case of 9a, with only methyl groups in 2- and 3-position of
the dihydropyridone ring, the strain between the substituents will
be lower and the kinetics of the aforementioned equilibration will
therefore be faster. According to the successful transformation of 9a
to its enolate by LDA (see Table 2) the equilibration between the
conformers seems to be fast enough in this case for the deproto-
nation to take place at a sufficient rate to avoid the side reactions
observed with 9d. But still, the kinetics of the equilibration of the
conformers of 9a are also of importance in this case since the ve-
locity of the addition of the 9a to LDA proved to be crucial to obtain
good yields of 10a, as mentioned above.
It is worth noting that the protonation of the enolates of 9a and
9d with either hydrochloric acid or ethyl salicylate resulted in
a high cis-stereoselectivity (Table 3). It is known from the diaster-
eoselective epimerization of trans-2,3-disubstituted cyclic ketones
that the proton source has a crucial influence on the diaster-
eoselectivity of epimerization reactions. Particularly, if the sub-
stituent at the 3-position of the keto group is small and, as
consequence, the substrate control is low. Then, specific reagents
for protonation, like ethyl salicylate, are required to gain high cis-
stereoselectivity.6 Interestingly, for the epimerization reactions of
the dihydropyridones 9 no substantial influence of the proton
sources on the diastereoselectivity was observed.
Diastereoselective epimerisation of the trans-2,3-disubstituted dihydropyridones 9a
and 9d employing LiHMDS as base
R1
N
R2
R1
N
R2
1) 2.0 equiv LiHMDS,
2 h, rt, THF
O
O
2
3
2 3
O
O
2) 1 h, rt
Ph
Ph
3) H+-source, -78 °C
9
10
Entry
9
R1
R2
Hþ-source
Product
10
Yieldd (%)
dra (10/9)
1
2
3
4
5
a
a
d
d
d
Me
Me
Ph
Ph
Ph
Me
Me
Bn
Bn
Bn
Ethyl salicylateb
2 M HClc
a
a
b
b
b
85
81
80
83
78
>99:1
99:1
92:8
94:6
97:3
Ethyl salicylateb
Ethyl salicylatec
2 M HClc
a
Determined via 1H NMR spectra.
The enolate of 9a and 9d, respectively, was added to a precooled solution
b
(ꢀ78 ꢁC) of the Hþ-source in THF.
c
Addition of the Hþ-source to the solution of the enolate of 9a and 9d,
respectively, at ꢀ78 ꢁC.
d
The yield refers to both diastereomers, if a mixture of diastereomers was
obtained.
applied to 9a with either reprotonation agent, ethyl salicylate or
aqueous hydrogen chloride, the diastereoselectivity actually not
only surpassed that of the transformation of 9d into 10b, the result
was also as excellent as with the above described method applying
LDA as base (Table 2).
We therefore had successfully developed a highly efficient
protocol for the synthesis of cis-2,3-disubstituted dihydropyridones
10 from the respective trans-configurated dihydropyridones 9 that
tolerates substrates of quite different steric demands.
As precursors for our synthesis of
b-amino acids, the N-un-
protected dihydropyridones 12 and 13 were required (Table 4).
Therefore, the N-benzoyl group present in 9 and 10 had to be re-
moved. This transformation had to be performed under carefully
controlled conditions to avoid epimerization of the stereocenter in
the a-position of the carbonyl group. At first, according to standard
procedures for such cleavage reactions, 9a was treated with
3.5 equiv of NaOMe at rt for 3.5 h.7a,b,10 This procedure, however,
yielded a mixture of 12a and its diastereomer 13a. As the meth-
anolysis of 9a turned out to be distinctly faster than the epimeri-
zation reaction only catalytic amounts of NaOMe were employed in
further experiments. Additionally, the reaction temperature was
lowered to 0 ꢁC, and the reaction was immediately stopped when
TLC indicated completion of the conversion. Under these modified
reaction conditions no epimerization occurred and the final prod-
uct could be obtained in a high yield (94%, Table 4, entry 1). These
reaction conditions also worked well for all other derivatives 9 and
10, providing the dihydropyridones 12b–d and 13a and 13b in di-
astereomeric pure form (1H NMR) and in almost quantitative yields
(94–98%, Table 4, entries 2–6).
The results obtained with the conversions of 9 with LDA on one
side and LiHMDS on the other gave an interesting insight into the
chemical behavior of 2,3-disubstituted N-acyl dihydropyridones. At
first, it is not astonishing that a kinetically inhibited reaction can be
initiated by raising the temperature, as was the case in the depro-
tonation reaction of 9d with LiHMDS that could not be effected at
ꢀ78 ꢁC but proceeded smoothly at rt. But, kinetic hindrance may
usually also be overcome by employing a stronger base instead of
increasing the temperature. However, LDA, a stronger base than
LiHMDS, did not only fail to accomplish the desired enolate for-
mation of 9d it also led to the decomposition of the starting com-
pound 9d at ꢀ78 ꢁC as well as at higher temperature such as 0 ꢁC.
As known from literature9 or from Table 2, LDA is usually a strong
enough base for the deprotonation of ketones at low temperature
(like ꢀ78 ꢁC). The failure of LDA in the present case might be at-
tributed to the position of the equilibrium between the different
conformers of 9d and the kinetics of their equilibration. In the
major conformer of 9d, the substituents at the 2- and 3-position
adopt each an pseudo axial orientation due to the strong A(1,3)
strain arising from the benzamide moiety R1 as discussed above
(Scheme 5). Accordingly, the proton at the 3-position of the major
conformer is in an equatorial position, e.g., roughly in plane with
the carbonyl function, and is therefore expected to show a low ki-
netic acidity. The equilibration between the major conformer and
the minor conformer, having both hydrogen atoms in a pseudo
axial position and therefore being more susceptible to deprotona-
tion, will proceed slowly at low temperatures as well. Depending on
the substituents, the equilibration between the conformers may be
much slower than the deprotonation reaction of the minor con-
former. As a consequence, the minor conformer of 9d, i.e., the
conformer more reactive toward deprotonation reactions, is lack-
ing. In the case of 9d, LDA seems not to be appropriate to deprot-
onate the major conformer in the 3-position as desired, but instead,
since the minor conformer is almost absent from the reaction
Table 4
Synthesis of N-unprotected dihydropyridones 12 and 13
R1
N
R2
R1
R2
O
2
3
2 3
cat. NaOMe
0 °C, MeOH
O
O
HN
O
O
Ph
9
12
R1
R2
R1
N
R2
O
2
3
cat. NaOMe
0 °C, MeOH
2 3
HN
Ph
10
13
Entry
Educt
R1
R2
NaOMe (equiv)
t (min)
Product
Yield (%)
1
2
3
4
5
6
9a
9b
9c
9d
10a
10b
Me
Me
Ph
Ph
Me
Ph
Me
0.3
0.5
0.5
0.5
0.3
0.5
30
35
40
70
45
75
12a
12b
12c
12d
13a
13b
94
98
95
95
96
95
Bn
Me
Bn
Me
Bn

M. Ege, K.T. Wanner / Tetrahedron 64 (2008) 7273–7282
7277
The relative configurations of 9, 10, 12, and 13 were determined
by their 1H NMR spectra. As mentioned above it is a general phe-
nomenon that substituents in the 2-position of 2-substituted N-
acyl-2,3-dihydropyridones adopt an axial orientation which is due
to the A(1,3) strain arising from the N-acyl group. As a consequence,
the JH2–3 coupling constants observed for hydrogen atoms in the 2-
and 3-positions of trans-2,3-disubstituted dihydropyridones
adopting an equatorial orientation are small (<1.2 Hz).11 The JH2–3
coupling constants found for 9a–d were between 0.0 and 1.3 Hz
providing clear evidence that these compounds possess trans-con-
figuration. For compounds 10a and 10b as epimers of 9a and 9d,
respectively, significantly larger JH2–3 coupling constants (5.6 Hz)
were observed, which is in accord with published data, confirming
the cis-configuration of these compounds.12 In the case of the N-
unprotected trans-2,3-disubstituted dihydropyridones 12, freed
from the N-acyl group and from the A(1,3) strain, the JH2–3 coupling
constants increased as expected to a significant extent. The dihy-
dropyridones 12a–c showed JH2–3 coupling constants between 11.0
and 13.7 Hz, typical values for trans-substituted compounds.13 The
JH2–3 coupling constant of 12d was somewhat lower (6.1 Hz), which
is likelyto be the resultof a ring distortion due tostericalinteractions
as twolarge substituents in 2- and 3-position are presentin this case.
Finally, 13a–b showed JH2–3 coupling constants between 4.5 and
5.4 Hz, which are typical values for cis-substituted compounds.13
The configurations assigned by 1H NMR spectroscopy were further
was then formed, but it was a mixture of the diastereomers 14 and
15, which most astonishingly, contained the trans-diastereomer 14
as the clearly predominating species in both cases (Table 5, entries
1 and 3).
As an excess of NaHMDS (1.15 equiv) had been applied in this
reaction it was assumed that the base that had remained after the
N-methylation had effected the isomerization. In a further experi-
ment, 12d was therefore treated with only 0.85 equiv of NaHMDS
while retaining all other conditions (treatment with NaHMDS at
ꢀ78 ꢁC followed by MeI and warming to rt, Table 5, entry 2). This
set up yielded the methylated trans-substituted diastereomer 14 in
diastereomeric pure form (1H NMR). Using the same method, the
2,3-cis-disubstituted compound 13b could be transformed without
a substantial loss of diastereomeric purity to 15 (14/15¼5:95, Table
5, entry 4). To determine whether the 82:18 mixture of 14 and 15
that had been obtained after treatment of 13b with 1.15 equiv of
NaHMDS followed by methyl iodide (Table 5, entry 3), possibly
reflects the thermodynamic equilibrium an additional experiment
was performed. Compound 14 was treated with 0.5 equiv of NaOMe
in THF at rt. After 25 h, the ratio between 14 and 15 was 89:11 and
remained almost unchanged after 93 h (87:13, Scheme 6). There-
fore, the result observed in the aforementioned N-alkylation ex-
periment (82:18) can be assumed to approximately reflect the
thermodynamic equilibrium.
Ph
Ph
Bn
confirmed by the structure of the
b
-amino acids 6 and 7, which were
Bn
0.5 equiv NaOMe
obtained from 12 and 13 in the subsequent transformation reactions
H3C N
O
H3C N
O
(see below, Table 6), which are well known in literature.14–17
rt, 93 h, THF
16 : 30 = 87 : 13
The transformation of dihydropyridones into
b
-amino acids had
14
15
already been applied successfully to compounds 2 being methyl-
ated at the nitrogen atom (Scheme 1).4 Therefore, it was interesting
to include the higher substituted N-methyl derivatives 14 or 15 in
this study as well. For the synthesis of 14 and 15, by N-methylation,
compounds 12d and 13b were treated with a slight excess of
NaHMDS at ꢀ78 ꢁC and subsequently with methyl iodide following
standard reaction conditions.15 At ꢀ78 ꢁC no reaction occurred,
however, in additional experiments the reaction mixtures, with 12d
and 13b, respectively, were therefore allowed to warm to rt after
methyl iodide had been added (Table 5, entries 1 and 3). A product
Scheme 6.
2,3-Substituted N-methyldihydropyridones are even better ac-
cessible via the corresponding 2-substituted N-methyl derivative,
e.g., 2a,4 by introducing the 3-subtituent at the end of the synthetic
sequence as exemplified by the preparation of 14 (Scheme 7).
Deprotonation of 2a4 with a slight excess of LiHMDS at ꢀ78 ꢁC,
similar to the procedures described for the benzylation of 8 (Table
1), followed by treatment with benzyl bromide (3 h at ꢀ78 ꢁC)
provided 15 in diastereomeric pure form and in a very high yield
(92%).
Table 5
Synthesis of 14 and 15 via N-methylation of 12d and 13b
Ph
N
Bn
Ph
N
1) 1.15 equiv LiHMDS,
1 h, -78 °C, THF
1) NaHMDS,
THF, 1 h, -78 °C
H3C
O
H3C
O
Ph
N
B
n
Ph
Bn
2) 2 equiv MeI, 2 h
2) 2 equiv BnBr,
3 h, -78 °C
-78 °C
rt
+
+
15
Me
Me
O
O
HN
O
O
d.r. > 99:1
92%
14
2a
12d
14
Scheme 7.
For the final step of the proposed b-amino acid synthesis, the
1) NaHMDS,
THF, 1 h, -78 °C
dihydropyridones 12–14 described above were subjected to an
oxidative ring cleavage procedure based on the use of sodium
periodate following our recently published reaction conditions for
this type of transformation4 (Table 6). Accordingly, aqueous solu-
tions of the respective compound, 12 and 13, were treated first with
sodium periodate and subsequently with sodium hydroxide at rt.
Purification by anion and subsequently by cation exchange chro-
matography provided the amino acids 6a–c$HCl and 7a$HCl in the
form of their hydrochlorides in good to quantitative yields (Table 6,
entries 1–3 and 5). The ring cleavage reactions proceeded without
any epimerization reaction, thereby yielding the final compounds
6a–c$HCl and 7a$HCl in diastereomerically pure form.
Ph
N
Bn
Ph
Bn
2) 2 equiv MeI, 2 h
-78 °C
rt
14
HN
15
13b
Entry
Educt
NaHMDS (equiv)
Product
Yieldb (%)
14/15a
1
2
3
4
12d
12d
13b
13b
1.15
0.85
1.15
0.85
92
93:7
>99:1
82:18
5:95
80c
88
81d
a
Assigned from 1H NMR spectra.
However, the situation was completely different when 12d and
13b were used as starting compounds. For these compounds, 12d
and 13b, the reaction rates were distinctly slower, the isolated
yields were lower, around 60%, and the obtained product showed
b
The yield refers to both diastereomers, if a mixture of diastereomers was
obtained.
c
Starting material 12d (13%) was reisolated.
Starting material 13b (12%) was reisolated.
d

7278
M. Ege, K.T. Wanner / Tetrahedron 64 (2008) 7273–7282
Table 6
Synthesis of
the trans-isomer obtained earlier. Importantly, for both steps, the
enolate alkylation as well as the stereoinversion, high diaster-
eoselectivities were observed. The oxidative ring opening to give the
b
-amino acid derivatives 6$HCl and 7$HCl
R1
R2
R1
R2
+
final
periodate as oxidant that had already proven useful in a related
synthesis of 3-monosubstituted -amino acids. A particular advan-
tage of the method introduced here is that the substituents in the
and -position of the -amino acid can be varied freely. It therefore
represents avaluable addition to literature methods.18 In the present
case, the final -amino acids were prepared as racemates only. But
b-amino acids could be efficiently effected employing sodium
2
3
1) 4.5 equiv NaIO4, t,
2) NaOH, rt
3) ion exchange resins
O
O
COOH
HN
H3N
Cl-
b
.
6 HCl
12
a
-
R1
R2
R1
R2
b
b
2
3
1) 4.5 equiv NaIO4, t,
2) NaOH, rt
3) ion exchange resins
+
H3N
COOH
HN
b
Cl-
the synthetic concept could be easily turned into an asymmetric
version using chiral N-acyliminium ion chemistry.
13
.
7 HCl
entry
Educt
R1
R2
Reaction times
Product
4. Experimental section
4.1. General methods
ta (h)
t
b (h)
Yieldc (%)
drd
1
2
3
4
5
6
12a
12b
12c
12d
13a
13b
Me
Me
Ph
Ph
Me
Ph
Me
Bn
Me
Bn
Me
Bn
2
22
22
65
2
24
65
65
65
24
65
6a$HCl
6b$HCl
6c$HCl
6d$HCl
7a$HCl
7b$HCl
94
83
81
57
94
61
>99:1
>99:1
>99:1
87:13
>99:1
95:5
THF was freshly distilled from sodium benzophenone ketyl
under nitrogen prior to use. Methanol was freshly distilled from
magnesium prior to use. Solvents for extraction and column
chromatography were distilled prior to use. Purchased chemical
reagents were used without further purification. The dihydropyr-
idones 2 and 8 were synthesized as described previously.4 Merck
silica gel (mesh 230–400) was used as stationary phase for column
chromatography (cc). Melting points: mps (uncorrected) were de-
termined using a Bu¨chi 510 Melting Point apparatus. Elementary
analysis: Elementaranalysator Rapid (Heraeus). IR spectroscopy:
FT-IR Spectrometer 1600 and Paragon 1000 (Perkin Elmer), oily
samples as film, solid samples as pellets for measurements. Mass
spectroscopy: Mass Spectrometer 5989 A with 59980 B particle
beam LC/MS interface (Hewlett Packard). NMR spectroscopy: NMR
spectra were recorded on JNMR-GX (Jeol, 400 MHz and 500 MHz)
with TMS as internal standard and integrated with the program of
NMR-software Nuts (2D Version 5.097, Acorn NMR, 1995).
65
a
For oxidation.
b
c
For hydrolysis.
The yield refers to both diastereomers, if a mixture of diastereomers was
obtained.
d
Determined via 1H NMR spectra.
some epimerisation (Table 6, entries 4 and 6). Interestingly, the cis-
2,3-disubstituted dihydropyridone 13b suffered significantly less
epimerisation in this reaction sequence than its trans-diastereomer
12d. Finally, the trisubstituted N-methyl derivative 14 completely
failed to undergo the transformation reaction to give the amino
acid 16, which is probably due to the higher substitution of this
compound and the steric demand associated with it (Scheme 8).
Ph
N
Bn
Ph
Bn
1) 4.5 equiv NaIO4, 65 h, rt
4.2. General procedure for the preparation of the trans-2,3-
disubstituted dihydropyridones 9a–d and 14 (GP1)
+
Me
O
Me NH2 COOH
Cl–
2) NaOH, 65 h, rt
3) ion exchange resins
14
16
A solution of the respective dihydropyridone 2b or 8a–d in THF
(0.08–0.1 M) was cooled to ꢀ78 ꢁC, and a solution of LiHMDS
(1.15 equiv, 1 M in THF) was added dropwise. After stirring at the
same temperature for 1 h, the alkylating reagent (3 equiv) was
added, and the reaction further treated as given. After quenching
with saturated brine, the mixture was extracted with EtOAc (3ꢂ).
The extracts were dried over Na2SO4 and evaporated under reduced
pressure. The residue was purified by cc to give the respective
dihydropyridone.
Scheme 8.
The results indicate the effect of the substitution pattern on the
outcome of the transformation reaction of dihydropyridones into
amino acids employing sodium periodate and sodium hydroxide.
When sterically demanding groups are present, the reaction is
slowed down and epimerization may occur. The latter is obviously
not a result of a reaction mechanism for the conversion of the
b
-
dihydropyridones into
b-amino acids that requires an enol or
enolate as intermediate. Otherwise epimerization would occur
more extensively and, particularly, would also occur with the less
hindered substrates 12a–c and 13a (Table 6, entries 1–3 and 5).
Therefore, the epimerization in the case of the transformation of
12d and 13b (Table 6, entries 4 and 6) is likely to be a competing
side reaction, which becomes significant only if the oxidation and
saponification sequence is extremely slow.
4.3. General procedure for the preparation of the N-H-2,3-
disubstituted dihydropyridones 12a–d and 13a–b (GP2)
A solution of NaOMe (0.3–0.5 equiv) in MeOH (0.16–0.35 M) was
added dropwise to an ice cooled solution of the respective dihy-
dropyridone 9a–d or 10a and 10b in MeOH (0.16–0.36 M). The
solution was stirred at 0 ꢁC for the time given. The solution was
neutralized with HCl (2 M) and concentrated in vacuo. The residue
was dissolved in brine and extracted with EtOAc (7ꢂ). The extract
was dried over Na2SO4 and evaporated under reduced pressure. The
residue was purified by cc to give the respective dihydropyridone
12a–d or 13a and 13b.
3. Conclusion
In summary, a synthetic concept for the diastereodivergent
synthesis of 2,3-disubstituted
idone derivatives as a synthetic equivalent for
b
-amino acids that uses dihydropyr-
-amino acids was
b
successfully implemented. In a key step of this new approach, 2-
substituted dihydropyridone derivatives are transformed into trans-
2,3-disubstituted derivatives by enolate alkylation and further into
the corresponding cis isomers by stereoinversion. The latter was
accomplished by kinetic reprotonation of the enolate formed from
4.4. General procedure for the purification of the b-amino
acid derivatives 6a–d$HCl and 7a,b$HCl (GP3)
The respective neutralized reaction mixture was adsorbed on an
acidic ion exchange resin (Amberlite IR 120). The resin was washed

M. Ege, K.T. Wanner / Tetrahedron 64 (2008) 7273–7282
7279
with distilled water until the washings were neutral and the free
4.4.3. (2RS,3SR)-1-Benzoyl-3-methyl-2-phenyl-2,3-dihydro-1H-
pyridin-4-one (9c)
amino acid was eluted with aqueous NH3 (20%). Following evapo-
ration, the residue was adsorbed on a basic ion exchange resin
(Amberlite IR 410). The resin was first washed with distilled water
until the washings were neutral, and then eluted with HCl (2 M).
Following evaporation, the respective amino acid hydrochloride
6a–d$HCl or 7a–b$HCl was obtained.
According to GP1 from 8b (2.10 g, 7.58 mmol) in 100 mL THF,
LiHMDS (8.70 mL, 8.7 mmol, 1 M in THF), and MeI (1.39 mL,
22.75 mmol). After addition of MeI, the cooling bath was removed
and the reaction mixture was warmed to rt slowly. The reaction
mixture was quenched 2 h after removal of the cooling bath. The
raw product contained 9c with ds>99:1 (1H NMR). Purification by
cc (PE/EtOAc 6:4) yielded 9c (1.98 g, 90%, ds>99:1, 1H NMR) as
4.4.1. (2RS,3RS)-1-Benzoyl-2,3-dimethyl-2,3-dihydro-1H-pyridin-
4-one (9a)
colorless solid: mp 87–88 ꢁC; 1H NMR (500 MHz, CDCl3)
d 1.46 (d,
A solution of 8a4 (1.00 g, 4.65 mmol) in 60 mL THF was cooled to
ꢀ78 ꢁC and a solution of LiHMDS (5.35 mL, 5.35 mmol, 1 M in THF)
was added dropwise. After stirring at the same temperature for 1 h,
J¼7.4 Hz, 3H), 2.94 (qt, J¼7.4, 0.9 Hz, 1H), 5.28 (dd, J¼8.3, 0.9 Hz,
1H), 5.71 (br s, 1H), 7.24–7.29 (m, 3H), 7.29–7.34 (m, 2H), 7.45–7.50
(m, 2H), 7.51–7.58 (m, 3H), 7.64 (d, J¼8.3 Hz, 1H); IR (KBr) 3069,
2924, 2852, 1659, 1594, 1494, 1447, 1423, 1342, 1265, 1215,
1150 cmꢀ1; MS (EI) m/z (rel intensity) 291 (Mþ, 23), 186 (22), 105
(100), 77 (33). Anal. Calcd for C19H17NO2: C, 78.33; H, 5.88; N, 4.81.
Found: C, 78.30; H, 5.72; N, 4.78.
MeI (872 mL, 14.00 mmol) was added. The cooling bath was re-
moved and the reaction mixture was allowed to warm to rt slowly;
2 h after removal of the cooling bath, the reaction mixture was
quenched with saturated brine, and the aqueous phase was
extracted with EtOAc (3ꢂ). The extracts were dried over Na2SO4
and evaporated under reduced pressure. The residue contained 9a
with ds>99:1 (1H NMR). Purification by column chromatography
on silica gel (cc) (PE/EtOAc 1:1) yielded 9a (970 mg, 91%, ds>99:1,
1H NMR) as colorless solid: mp 108–109 ꢁC; 1H NMR (400 MHz,
4.4.4. (2RS,3SR)-1-Benzoyl-3-benzyl-2-phenyl-2,3-dihydro-
1H-pyridin-4-one (9d)
A solution of 8b4 (1.00 g, 3.60 mmol) in 36 mL THF was cooled to
ꢀ78 ꢁC and a solution of LiHMDS (4.10 mL, 4.10 mmol, 1 M in THF)
was added dropwise. After stirring at the same temperature for 1 h,
BnI (2.35 g, 10.8 mmol) was added. After stirring for 24 h at ꢀ78 ꢁC,
the reaction mixture was quenched with saturated brine and
warmed to rt. The aqueous phase was separated and extracted with
EtOAc (3ꢂ). The extracts were dried over Na2SO4 and evaporated
under reduced pressure. The residue contained 9d with ds>99:1
(1H NMR). Purification by cc (PE/EtOAc 7:3) yielded 9d (1.22 g, 92%,
CDCl3)
d
1.28 (d, J¼7.4 Hz, 3H), 1.33 (d, J¼6.8 Hz, 3H), 2.18 (qt, J¼7.4,
1.3 Hz, 1H), 4.66 (qd, J¼6.8, 1.3 Hz, 1H), 5.21 (dd, J¼8.2, 1.3 Hz, 1H),
7.36 (d, J¼8.2 Hz, 1H), 7.45–7.58 (m, 5H); IR (KBr) 2922, 1657, 1636,
1341, 630 cmꢀ1; MS (EI) m/z (rel intensity) 229 (Mþ, 14),124 (8), 105
(100), 77 (34). Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11.
Found: C, 73.29; H, 6.59; N, 6.15.
1
4.4.2. (2RS,3RS)-1-Benzoyl-3-benzyl-2-methyl-2,3-dihydro-1H-
pyridin-4-one (9b)
(A) According to GP1 from 8a (50 mg, 0.23 mmol) in 2.5 mL
THF, LiHMDS (246 mL, 0.26 mmol, 1 M in THF), and BnI (150 mg,
0.69 mmol). The alkylation was performed by stirring the reaction
mixture at ꢀ78 ꢁC for 29 h. The raw product contained 9b with
ds>99:1 (1H NMR). Purification by cc (PE/EtOAc 7:3) yielded 9b
(68 mg, 96%, ds>99:1, 1H NMR) as colorless solid: mp 84–85 ꢁC; 1H
ds>99:1, H NMR) as colorless solid: mp 139–140 ꢁC; 1H NMR
(400 MHz, CDCl3)
d
2.90 (dd, J¼13.3, 10.8 Hz, 1H), 3.07 (dd, J¼10.8,
4.6 Hz, 1H), 3.16 (dd, J¼13.3, 4.6 Hz, 1H), 5.37 (d, J¼8.4 Hz, 1H), 5.66
(br s, 1H), 7.11 (d, J¼7.0 Hz, 2H), 7.19–7.30 (m, 6H), 7.33 (t, J¼7.2 Hz,
2H), 7.41–7.60 (m, 5H), 7.63–7.78 (m,1H); IR (KBr) 3026, 2926,1680,
1660, 1592, 1494, 1448, 1423, 1345, 1272, 1210, 1148, 699 cmꢀ1; MS
(EI) m/z (rel intensity) 367 (Mþ, 14), 276 (10), 262 (30), 193 (42), 115
(15), 105 (100), 77 (58). Anal. Calcd for C25H21NO2: C, 81.72; H, 5.76;
N, 3.81. Found: C, 81.44; H, 5.69; N, 3.74.
NMR (500 MHz, CDCl3)
d
1.26 (d, J¼6.7 Hz, 3H), 2.53 (ddt, J¼10.5,
4.8, 1.2 Hz, 1H), 2.77 (dd, J¼13.7, 10.5 Hz, 1H), 3.00 (dd, J¼13.7,
4.8 Hz, 1H), 4.69 (q, J¼6.7 Hz, 1H), 5.29 (dd, J¼8.2, 1.2 Hz, 1H), 7.11–
7.18 (m, 2H), 7.24 (tt, J¼7.4, 1.6 Hz, 1H), 7.30 (tt, J¼7.4, 1.6 Hz, 2H),
7.37–7.39 (m, 1H), 7.47–7.53 (m, 4H), 7.57 (m, 1H); IR (KBr) 3070,
3024, 2922, 1658, 1587, 1495, 1450, 1423, 1336, 1276, 1216, 1151,
704 cmꢀ1; MS (CI) m/z (rel intensity) 306 (MHþ, 100), 105 (7). Anal.
Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found: C, 78.56; H,
6.22; N, 4.62. (B) A solution of 8a (50 mg, 0.23 mmol) in 2.5 mL
4.4.5. (2RS,3SR)-1-Benzoyl-2,3-dimethyl-2,3-dihydro-1H-pyridin-
4-one (10a)
(A) A solution of 9a (400 mg, 1.74 mmol) in 14 mL THF was
added to a solution of LiHMDS (3.50 mL, 3.50 mmol, 1 M in THF) for
2 h at rt. Following stirring for 1 h, this solution was added to
a
precooled solution (ꢀ78 ꢁC) of ethyl salicylate (1.28 mL,
8.70 mmol, 0.73 M in THF). After stirring for 1 h at ꢀ78 ꢁC, glacial
THF was cooled to ꢀ78 ꢁC and a solution of LiHMDS (250
mL,
acetic acid (400 mL, 6.90 mmol) was added and the reaction mixture
0.25 mmol, 1 M in THF) was added dropwise. After stirring at the
same temperature for 1 h, benzyl bromide (82 mL, 0.69 mmol) was
was warmed up to rt. On addition of EtOAc, the solution was
washed with saturated NaHCO3 and brine. The aqueous layers were
extracted with EtOAc (3ꢂ). The combined organic layers dried over
Na2SO4 and evaporated under reduced pressure. The residue con-
tained 10a with ds>99:1 (1H NMR). The residue was purified by cc
(PE/EtOAc 1:1) to give 10a (340 mg, 85%, ds>99:1, 1H NMR) as
colorless solid. (B) A solution of 9a (46 mg, 0.20 mmol) in 1.6 mL
added. The cooling bath was removed and the reaction mixture
was allowed to warm to rt slowly; 1.25 h after removal of the
cooling bath, the reaction mixture was quenched with saturated
brine. The aqueous phase was separated and extracted with EtOAc
(3ꢂ). The extracts were dried over Na2SO4 and evaporated under
reduced pressure. The residue contained 9b with ds>99:1 (1H
NMR). Purification by cc (PE/EtOAc 7:3) yielded 9b (58 mg, 81%,
ds>99:1, 1H NMR) and 11 (9 mg, 10%), each as colorless solid.
THF was added to a solution of LiHMDS (400 mL, 0.40 mmol, 1 M in
THF) for 2 h at rt. Following stirring for 1 h, the solution was cooled
to ꢀ78 ꢁC and quenched with HCl (1.0 mL, 2 M). The reaction
mixture was warmed to rt slowly and washed with saturated
NaHCO3. The aqueous phase was extracted with EtOAc and dried
over Na2SO4 as described under (A). The residue contained 10a with
ds>99:1 (1H NMR). Purification by cc (PE/EtOAc 1:1) yielded 10a
(37 mg, 81%, ds>99:1, 1H NMR) as colorless solid. (C) A solution of
9a (50 mg, 0.22 mmol) in 1.5 mL THF was added to a solution of LDA
Compound 11: mp 108–109 ꢁC; 1H NMR (500 MHz, CDCl3)
d 1.44
(d, J¼6.7 Hz, 3H), 2.88 (d, J¼15.4 Hz, 1H), 2.96 (d, J¼14.1 Hz, 1H),
3.09 (d, J¼14.1 Hz, 1H), 3.25 (d, J¼15.4 Hz, 1H), 4.99 (q, J¼6.7 Hz,
1H), 5.36 (d, J¼8.0 Hz, 1H), 7.04–7.10 (m, 2H), 7.20–7.37 (m, 11H),
7.43 (t, J¼7.9 Hz, 2H), 7.52 (tt, J¼7.5, 1.3 Hz, 1H); IR (KBr) 3060,
3028, 2929, 2851, 1667, 1597, 1494, 1450, 1422, 1335, 1276, 1154,
699 cmꢀ1; MS (EI) m/z (rel intensity): 395 (Mþ, 100), 380 (53), 366
(19), 343 (20), 329 (26), 319 (100); HRMS (EI) calcd for C27H25NO2
(Mþ) 395.1885, found 395.1874.
[prepared from diisopropylamine (62 mL, 0.44 mmol) and n-BuLi
(275 mL, 0.44 mmol, 1.6 M in hexane)] in 1 mL THF for 12 min at
ꢀ78 ꢁC. After stirring for 1 h at ꢀ78 ꢁC, the reaction mixture was

7280
M. Ege, K.T. Wanner / Tetrahedron 64 (2008) 7273–7282
added to a precooled solution (ꢀ78 ꢁC) of ethyl salicylate (162
m
L,
3.38 (dqd, J¼11.0, 6.5, 1.5 Hz, 1H), 4.98 (d, J¼7.5 Hz, 1H), 5.04 (br s,
1H), 7.10 (t, J¼7.5 Hz, 1H); IR (KBr) 3427, 2923, 2854, 1636,
1023 cmꢀ1; MS (EI) m/z (rel intensity) 125 (Mþ, 79), 110 (25), 96
(18), 82 (28), 70 (100). Anal. Calcd for C7H11NO: C, 67.17; H, 8.86; N,
11.19. Found: C, 66.96; H, 8.87; N, 11.11.
1.10 mmol) in 1.5 mL THF and finally quenched with glacial acetic
acid (51 mL, (0.88 mmol) according to (A)). After work up as de-
scribed under (A), the raw product contained 10a with ds>99:1 (1H
NMR). After purification of the raw product by cc (PE/EtOAc 1:1)
10a was obtained (42 mg, 82%, ds>99:1, 1H NMR) as colorless solid.
(D) A solution of 9a (50 mg, 0.22 mmol) in 1.5 mL THF was added to
4.4.8. (2RS,3RS)-3-Benzyl-2-methyl-2,3-dihydro-1H-pyridin-4-one
(12b)
a
solution of LDA [prepared from diisopropylamine (62
mL,
0.44 mmol) and n-BuLi (275 L, 0.44 mmol, 1.6 M in hexane)] in
m
According to GP2 from 9b (800 mg, 2.62 mmol) in 17 mL MeOH,
Na (32 mg,1.39 mmol) in 4 mL MeOH, reaction time 35 min. The raw
product contained 12b with ds>99:1 (1H NMR). Purification by cc
(CH2Cl2/MeOH 9.5:0.5) yielded 12b (517 mg, 98%, ds>99:1, 1H NMR)
1 mL THF for 12 min at ꢀ78 ꢁC. After stirring for 1 h at ꢀ78 ꢁC, the
reaction mixture was quenched with HCl (1.0 mL, 2 M) according to
(B). After work up as described under (B), the raw product con-
tained 10a with ds>99:1 (1H NMR). After purification of the raw
product by cc (PE/EtOAc 1:1) 10a was obtained (43 mg, 83%,
as colorless solid: mp 113–114 ꢁC; 1H NMR (400 MHz, CDCl3)
d 1.17
(d, J¼6.7 Hz, 3H), 2.34–2.37 (m, 1H), 2.79 (dd, J¼13.8, 10.4 Hz, 1H),
3.00 (dd, J¼13.8, 4.5 Hz, 1H), 3.40–3.45 (m, 1H), 4.97 (br s, 1H), 5.01
(d, J¼7.4 Hz, 1H), 7.07 (t, J¼7.4 Hz, 1H), 7.18–7.24 (m, 3H), 7.26–7.31
(m, 2H); IR (KBr) 3253, 3020, 2967, 2922,1616,1573,1512,1443,1401,
1241 cmꢀ1; MS (EI, 70 eV); m/z (rel intensity): 201 (Mþ, 88),186 (21),
158 (13), 124 (31), 117 (100), 110 (59), 91 (69). Anal. Calcd for
1
ds¼99:1, H NMR) as colorless solid: mp 111–112 ꢁC; 1H NMR
(500 MHz, CDCl3)
d
1.15 (d, J¼7.0 Hz, 3H),1.20 (d, J¼6.7 Hz, 3H), 2.98
(qd, J¼7.0, 5.6 Hz, 1H), 4.83–4.87 (m, 1H), 5.25 (d, J¼8.1 Hz, 1H), 7.33
(d, J¼8.1 Hz, 1H), 7.44–7.64 (m, 5H); IR (KBr) 3076, 2968, 2931,
2873, 1661, 1592, 1448, 1427, 1349, 1307, 1257, 1212, 1156,
1080 cmꢀ1; MS (CI) m/z (rel intensity) 230 [MHþ] (100), 126 (14),
105 (56). Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11.
Found: C, 73.42; H, 6.15; N, 6.15.
C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C, 77.28; H, 7.50; N, 6.93.
4.4.9. (2RS,3SR)-3-Methyl-2-phenyl-2,3-dihydro-1H-pyridin-4-one
(12c)
4.4.6. (2RS,3SR)-1-Benzoyl-3-benzyl-2-phenyl-2,3-dihydro-1H-
pyridin-4-one (10b)
According to GP2 from 9c (1.00 g, 3.43 mmol) in 21 mL MeOH,
Na (40 mg, 1.74 mmol) in 5 mL MeOH, reaction time 40 min. The
raw product contained 12c with ds>99:1 (1H NMR). Purification by
cc (CH2Cl2/MeOH 9.5:0.5) yielded 12c (610 mg, 95%, ds>99:1, 1H
NMR) as colorless solid: mp 174–175 ꢁC; 1H NMR (500 MHz, CDCl3)
(A) A solution of 9d (46 mg, 0.13 mmol) in 1.5 mL THF was added
to a solution of LiHMDS (250 mL, 0.25 mmol,1 M in THF) for 2 h at rt.
Following stirring for 1 h, the solution was cooled to ꢀ78 ꢁC and
quenched with ethyl salicylate (92
mL, 0.60 mmol) in 1.0 mL THF.
d
0.94 (d, J¼6.9 Hz, 3H), 2.63–2.70 (m, 1H), 4.29 (d, J¼13.7 Hz, 1H),
After stirring for 1 h at the same temperature, glacial acetic acid
(29 L, 0.50 mmol) wasadded andthe reaction mixturewaswarmed
4.96 (br s, 1H), 5.12 (dd, J¼7.3, 1.2 Hz, 1H), 7.21 (t, J¼7.3 Hz, 1H),
7.33–7.41 (m, 5H); IR (KBr) 3303, 3060, 3032, 2967, 2926, 1558,
1231, 1183, 768, 700 cmꢀ1; MS (EI) m/z (rel intensity) 187 (Mþ, 66),
118 (100), 117 (87), 91 (21). Anal. Calcd for C12H13NO: C, 76.98; H,
7.00; N, 7.48. Found: C, 76.76; H, 6.95; N, 7.55.
m
up to rt. On addition of EtOAc, the solution was washed with satu-
rated NaHCO3 and brine. The aqueous layers were extracted with
EtOAc (3ꢂ). The combined organic layers dried over Na2SO4 and
evaporated under reduced pressure. The residue contained 10b with
ds 94:6 (1H NMR). Purification by cc (PE/EtOAc¼7:3) yielded 10b
(38 mg, 83%, ds¼94:6,1H NMR) as colorless solid. (B) A solution of 9d
(46 mg, 0.13 mmol) in 1.5 mLTHF was added to a solution of LiHMDS
4.4.10. (2RS,3SR)-3-Benzyl-2-phenyl-2,3-dihydro-1H-pyridin-4-
one (12d)
According to GP2 from 9d (400 mg, 1.09 mmol) in 7 mL MeOH,
Na (13 mg, 0.56 mmol) in 3 mL MeOH, reaction time 70 min. The
raw product contained 12d with ds>99:1 (1H NMR). Purification by
cc (CH2Cl2/MeOH 9.5:0.5) yielded 12d (274 mg, 95%, ds>99:1, 1H
NMR) as colorless solid: mp 129–130 ꢁC; 1H NMR (500 MHz, CDCl3)
(250 mL, 0.25 mmol, 1 M in THF) for 2 h at rt. Following stirring for
1 h, the solution was cooled to ꢀ78 ꢁC and quenched with HCl
(1.0 mL, 2 M). The reaction mixture was warmed to rt slowly and
washed with saturated NaHCO3. The aqueous phase was extracted
with EtOAc (3ꢂ). The combined organic layers dried over Na2SO4
and evaporated under reduced pressure. The raw product contained
10b with ds>97:3 (1H NMR). Purification by cc (PE/EtOAc 7:3) yiel-
ded 10b (36 mg, 78%, ds¼97:3, 1H NMR) as colorless solid: mp 224–
d
2.85–2.93 (m, 2H), 2.97–3.03 (m, 1H), 4.38 (dd, J¼6.1, 2.4 Hz, 1H),
5.10 (d, J¼7.5 Hz, 1H), 5.22 (br s, 1H), 7.07–7.32 (m, 11H); IR (KBr)
3222, 3025, 2922, 1621, 1564, 1521, 1211, 1174, 698 cmꢀ1; MS (EI) m/
z (rel intensity) 263 (Mþ, 100), 193 (30), 172 (53), 115 (42), 106 (66),
91 (53), 77 (20). Anal. Calcd for C18H17NO: C, 82.10; H, 6.51; N, 5.32.
Found: C, 81.88; H, 6.52; N, 5.28.
225 ꢁC; 1H NMR (500 MHz, CDCl3)
d
2.24 (dd, J¼14.3, 9.5 Hz, 1H),
3.47–3.59 (m, 2H), 5.44 (d, J¼8.3 Hz, 1H), 5.74 (d, J¼5.6 Hz, 1H), 7.06
(d, J¼7.2 Hz, 2H), 7.17–7.45 (m, 12H), 7.45–7.58 (m, 2H); IR (KBr)
3060, 3027, 2924, 1663, 1596, 1493, 1446, 1422, 1329, 1225, 1147,
697 cmꢀ1; MS (EI) m/z (rel intensity) 367 (Mþ, 21), 262 (64),193 (79),
115 (24), 105 (100), 77 (85). Anal. Calcd for C25H21NO2: C, 81.72; H,
5.76; N, 3.81. Found: C, 81.57; H, 5.76; N, 3.74.
4.4.11. (2RS,3SR)-2,3-Dimethyl-2,3-dihydro-1H-pyridin-4-one
(13a)
According to GP2 from 10a (230 mg,1.00 mmol) in 6.5 mL MeOH,
Na (7 mg, 0.30 mmol) in 1.6 mL MeOH, reaction time 45 min. The
raw product contained 13a with ds>99:1 (1H NMR). Purification by
cc (CH2Cl2/MeOH 9.5:0.5) yielded 13a (120 mg, 96%, ds>99:1, 1H
NMR) as colorless solid: mp 74–75 ꢁC; 1H NMR (400 MHz, CDCl3)
4.4.7. (2RS,3RS)-2,3-Dimethyl-2,3-dihydro-1H-pyridin-4-one (12a)
A solution of NaOMe in MeOH prepared by addition of Na
(15 mg, 0.65 mmol) to 4 mL MeOH was added dropwise to an ice
cooled solution of 9a (500 mg, 2.18 mmol) in 6 mL MeOH. The so-
lution was stirred at 0 ꢁC for 30 min before it was neutralized with
HCl (2 M) and concentrated in vacuo. The residue was dissolved in
brine and extracted with EtOAc (7ꢂ). The extract was dried over
Na2SO4 and evaporated under reduced pressure. The residue con-
taining 12a with ds>99:1 (1H NMR) was purified by cc (CH2Cl2/
MeOH 9.5:0.5) to give 12a (256 mg, 94%, ds>99:1, 1H NMR) as
d
1.00 (d, J¼7.3 Hz, 3H),1.20 (d, J¼6.6 Hz, 3H), 2.22 (qd, J¼7.3, 4.5 Hz,
1H), 3.74–3.80 (m, 1H), 4.91 (d, J¼7.3 Hz, 1H), 5.26 (br s, 1H), 7.10 (t,
J¼7.3 Hz,1H); IR (KBr) 3278, 2925,1618,1238 cmꢀ1; MS (CI) m/z (rel
intensity) 126 (MHþ,100). Anal. Calcd for C7H11NO: C, 67.17; H, 8.86;
N, 11.19. Found: C, 67.16; H, 8.87; N, 11.13.
4.4.12. (2RS,3RS)-3-Benzyl-2-phenyl-2,3-dihydro-1H-pyridin-4-
one (13b)
AccordingtoGP2from10b (200 mg, 0.54 mmol) in 3.5 mL MeOH,
Na (6 mg, 0.26 mmol) in 1.5 mL MeOH, reaction time 75 min. The
colorless solid: mp 68–69 ꢁC; 1H NMR (500 MHz, CDCl3)
J¼7.0 Hz, 3H), 1.30 (d, J¼6.5 Hz, 3H), 2.17 (dq, J¼11.0, 7.0 Hz, 1H),
d
1.19 (d,

M. Ege, K.T. Wanner / Tetrahedron 64 (2008) 7273–7282
7281
raw product contained 13b with ds>99:1 (1H NMR). Purification by
cc (CH2Cl2/MeOH 9.5:0.5) yielded 13b (135 mg, 95%, ds>99:1, 1H
NMR) as colorless solid: mp 141–142 ꢁC; 1H NMR (500 MHz, CDCl3)
(30 mg, 0.10 mmol) in 1 mL THF at rt. After stirring for 93 h, the
reaction mixture was quenched with 2 M NaOH. The aqueous layer
was extracted with EtOAc (3ꢂ). The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in vacuo.
The residue contained 14 and 15 in a ratio of 87:13 (1H NMR).
d
2.47 (dd, J¼14.2, 7.1 Hz, 1H), 2.92–2.99 (m, 1H), 3.08 (dd, J¼14.2,
7.6 Hz, 1H), 4.77 (dd, J¼5.4, 1.4 Hz, 1H), 5.05 (br s, 1H), 5.12 (d,
J¼7.4 Hz, 1H), 6.91–6.95 (m, 2H), 7.13 (tt, J¼7.3, 1.3 Hz, 1H), 7.15–7.19
(m, 2H), 7.19–7.24 (m, 1H), 7.31–7.40 (m, 5H); IR (KBr) 3190, 3021,
2926, 1623, 1565, 1214, 699 cmꢀ1; MS (EI) m/z (rel intensity) 263
(Mþ,100),193 (33),179 (24),172 (52),158 (16),144 (12),130 (20),115
(43), 106 (77), 91 (65), 77 (21). Anal. Calcd for C18H17NO: C, 82.10; H,
6.51; N, 5.32. Found: C, 81.84; H, 6.43; N, 5.29.
4.4.16. (2RS,3RS)-3-Amino-2-methylbutyric acid hydrochloride
(6a$HCl)
NaIO4 (376 mg, 1.76 mmol) was added to a solution of 12a
(50 mg, 0.38 mmol) in H2O (3.0 mL) at rt and after stirring for 2 h,
NaOH (3.0 mL, 15.7 M) was added. After stirring for 24 h at rt, the
reaction mixture was neutralized with HCl (6 M) and adsorbed on
an acidic ion exchange resin (Amberlite IR 120). The resin was
washed with distilled water until the washings were neutral and
the free amino acid was eluted with aqueous NH3 (20%). Following
evaporation, the residue was adsorbed on a basic ion exchange
resin (Amberlite IR 410). The resin was first washed with distilled
water until the washings were neutral, and then eluted with HCl
(2 M). Following evaporation, the amino acid hydrochloride 6a$HCl
(55 mg, 94%, ds>99:1, 1H NMR) was obtained as colorless solid: mp
4.4.13. (2RS,3SR)-3-Benzyl-1-methyl-2-phenyl-2,3-dihydro-1H-
pyridin-4-one (14)
(A) NaHMDS (48 mL, 0.10 mmol, 2 M in THF) was added to a so-
lution of 12d (30 mg, 0.11 mmol) in 1.5 mL THF at ꢀ78 ꢁC. Following
stirring for 1 h, methyl iodide (14 mL, 0.33 mmol) was added, the
cooling bath was removed, and the mixture was stirred for 2 h. The
reaction mixture was quenched with 2 M NaOH. The aqueous layer
was extracted with EtOAc (3ꢂ). The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in vacuo.
The residue contained 14 and 12d each with ds>99:1 (1H NMR).
Purification by cc (CH2Cl2/MeOH 9.5:0.5) yielded 14 (25 mg, 80%,
ds>99:1, 1H NMR) and 12d (4 mg, 13%, ds>99:1, 1H NMR) as col-
orless solid. (B) According to GP1 from 2b (300 mg, 1.60 mmol) in
21 mL THF, LiHMDS (1.85 mL, 1.85 mmol, 1 M in THF) and BnBr
207–209 ꢁC (lit. mp16 221–222 ꢁC); 1H NMR (400 MHz, D2O)
d 1.09
(d, J¼7.2 Hz, 3H), 1.12 (d, J¼6.6 Hz, 3H), 2.59–2.63 (m, 1H), 3.43–
3.46 (m, 1H); IR (KBr) 1655, 1618, 1406, 1338 cmꢀ1; MS (CI) m/z (rel
intensity) 118 (MꢀClꢀ, 100). The analytical data are in accord with
published data.16
(580
m
L, 4.80 mmol). The alkylation was performed by stirring the
4.4.17. (2RS,3RS)-3-Amino-2-benzylbutyric acid hydrochloride
(6b$HCl)
reaction mixture at ꢀ78 ꢁC for 2 h. The raw product contained 14
with ds>99:1 (1H NMR). Purification by cc (CH2Cl2/MeOH, 9.5:0.5)
yielded 14 (408 mg, 92%, ds>99:1, 1H NMR) as colorless solid: mp
NaIO4 (213 mg, 1.00 mmol) was added to a solution of 12b
(40 mg, 0.19 mmol) in H2O (1.4 mL) at rt and after stirring for 22 h,
aqueous NaOH (0.65 mL, 12.6 M) was added. After stirring for 65 h
at rt, the reaction mixture was neutralized with HCl (6 M) and
purified according to GP3 yielding the amino acid hydrochloride
6b$HCl (35 mg, 83%, ds>99:1, 1H NMR) as colorless solid. The amino
acid hydrochloride 6b$HCl was transformed to the corresponding
free amino acid using the acidic ion exchange resin Amberlite IR
120 for comparison with the published analytical data of the free
amino acid of 6b$HCl: mp 219–222 ꢁC (lit. mp16 218–219 ꢁC); 1H
77–78 ꢁC; 1H NMR (500 MHz, CDCl3)
d
2.67 (dddd, J¼11.3, 4.2, 1.9,y
0.9 Hz, 1H), 2.77 (dd, J¼13.6, 11.3 Hz, 1H), 2.99 (s, 3H), 3.15 (dd,
J¼13.6, 4.2 Hz, 1H), 4.06 (d, J¼1.9 Hz,y 1H), 4.97 (dd, J¼7.5, 0.9 Hz,
1H), 6.96–7.00 (m, 2H), 7.13 (dd, J¼7.5 Hz, 1H), 7.18–7.29 (m, 6H),
7.35 (t, J¼7.3 Hz, 2H); IR (KBr) 3028, 2949, 2905, 1641, 1594, 1490,
1448, 1422, 1344, 1173, 781, 750, 703 cmꢀ1; MS (EI) m/z (rel in-
tensity) 277 (Mþ, 100), 200 (14), 193 (43), 186 (36), 178 (20), 146
(25),115 (49), 91 (60). Anal. Calcd for C19H19NO: C, 82.28; H, 6.90; N,
5.05. Found: C, 81.93; H, 7.20; N, 5.06.
NMR (500 MHz, D2O)
d
1.39 (d, J¼6.8 Hz, 3H), 2.70 (dt, J¼9.5, 5.6 Hz,
1H), 2.93 (dd, J¼13.6, 9.5 Hz,1H), 2.99 (dd, J¼13.6, 5.6 Hz,1H), 3.48–
3.52 (m, 1H), 7.28–7.33 (m, 3H), 7.36–7.41 (m, 2H); IR (KBr) 1650,
1632, 1432 cmꢀ1; MS (CI) m/z (rel intensity) 194 (MHþ, 100). The
analytical data are in accord with published data.16
4.4.14. (2RS,3RS)-3-Benzyl-1-methyl-2-phenyl-2,3-dihydro-1H-
pyridin-4-on (15)
NaHMDS (39 mL, 0.08 mmol, 2 M in THF) was added to a solution
of 13b (25 mg, 0.09 mmol) in 1.5 mL THF at ꢀ78 ꢁC. Following stir-
ring for 1 h, methyl iodide (12
ml, 0.28 mmol) was added, the cooling
4.4.18. (2RS,3SR)-3-Amino-2-methyl-3-phenylpropionic acid
hydrochloride (6c$HCl)
bath was removed, and the mixture was stirred for 2 h. The reaction
mixture was quenched with 2 M NaOH. The aqueous layer was
extracted with EtOAc (3ꢂ). The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in vacuo.
The residue contained 15 with ds>95:5 and 13b with ds>99:1 (1H
NMR). Purification by cc (CH2Cl2/MeOH 9.5:0.5) yielded 15 (21 mg,
81%, ds¼95:5, 1H NMR) and 13b (3 mg, 12%, ds>99:1, 1H NMR) as
NaIO4 (214 mg, 1.00 mmol) was added to a solution of 12c
(40 mg, 0.21 mmol) in 1.4 mL H2O and 0.7 mL THF at rt and after
stirring for 22 h, aqueous NaOH (0.90 mL, 10.0 M) was added. After
stirring for 65 h at rt, the reaction mixture was neutralized with HCl
(6 M) and purified according to GP3 yielding the amino acid
hydrochloride 6c$HCl (31 mg, 81%, ds>99:1, 1H NMR): mp 242–
colorless solid. Compound 15: 1H NMR (500 MHz, CDCl3)
d
2.07 (dd,
244 ꢁC; 1H NMR (500 MHz, CD3OD)
d
1.04 (d, J¼7.1 Hz, 3H), 3.08
J¼14.7, 10.9 Hz, 1H), 2.84 (s, 3H), 3.49 (ddd, J¼10.9, 7.6,y 3.8 Hz, 1H),
3.58 (dd, J¼14.7, 3.8 Hz,1H), 4.06 (d, J¼7.6 Hz,y 1H), 5.00 (d, J¼7.5 Hz,
1H), 6.90 (d, J¼7.5 Hz, 1H), 7.00 (d, J¼7.5 Hz, 2H), 7.19–7.36 (m, 8H).
(dq, J¼9.9, 7.1 Hz, 1H), 4.24 (d, J¼9.9 Hz, 1H), 7.41–7.53 (m, 5H); IR
(KBr) 1721, 1595, 1514, 1204 cmꢀ1; MS (CI) m/z (rel intensity) 180
(MꢀClꢀ, 100), 163 (92), 107 (23). The NMR and IR data are in accord
with data published for the respective enantiomeric pure
product.14
4.4.15. Equilibration between (2RS,3SR)-3-benzyl-1-methyl-2-
phenyl-2,3-dihydro-1H-pyridin-4-one (14) and (2RS,3RS)-3-benzyl-
1-methyl-2-phenyl-2,3-dihydro-1H-pyridin-4-on (15)
4.4.19. (2RS,3SR)-3-Amino-2-benzyl-3-phenylpropionic acid
hydrochloride (6d$HCl)
A solution of MeOH (4 mL, 0.10 mmol) and NaHMDS (25 mL,
0.05 mmol, 2 M in THF) in 1 mL THF was added to a solution of 14
NaIO4 (223 mg, 1.08 mmol) was added to a solution of 12d
(60 mg, 0.22 mmol) in 1.5 mL H2O and 1.5 mL THF at rt and after
stirring for 65 h, aqueous NaOH (0.65 mL, 16.9 M) was added. After
stirring for 65 h at rt, the reaction mixture was neutralized with HCl
(6 M) and purified with a acidic ion exchange resin (Amberlite IR
y
Compound should adopt a bisaxial conformation due to the A(1,2) strain be-
tween substituents in 1- and 2-position.

7282
M. Ege, K.T. Wanner / Tetrahedron 64 (2008) 7273–7282
120) as described in GP3. The residue of the eluate with aqueous
NH3 (20%) was dissolved in HCl (1 M) and washed with EtOAc (5ꢂ).
The aqueous phase was neutralized and further purified on
Amberlite IR 410 as described in GP3. The amino acid hydrochlo-
rides 6d$HCl and 7a$HCl were obtained in a ratio of 87:13 (1H NMR)
(31 mg, 57% referring to 6d$HCl and 7a$HCl) as a colorless solid
(31 mg, 57%, ds¼87:13, 1H NMR): mp 224–226 ꢁC (lit.19 mp 227 ꢁC);
236–237 ꢁC); 1H NMR (500 MHz, D2O)
d
2.77 (dd, J¼13.6, 10.7 Hz,
1H), 2.92 (dd, J¼13.6, 5.2 Hz, 1H), 3.24 (ddd, J¼10.7, 8.6, 5.2 Hz, 1H),
4.42 (d, J¼8.6 Hz, 1H), 7.07–7.31 (m, 10H); IR (KBr) 1720, 1620,
1525 cmꢀ1; MS (CI) m/z (rel intensity) 256 (MꢀClꢀ, 84), 161 (60),
106 (100). The NMR and IR data are in accord with data published
for the respective enantiomeric pure product.17
1H NMR (400 MHz, D2O)
d
2.56 (dd, J¼13.9, 9.3 Hz, 1H), 2.62 (dd,
Acknowledgements
J¼13.9, 4.8 Hz, 1H), 3.17–3,22 (m, 1H), 4.37 (d, J¼9.7 Hz, 1H), 6.88–
6.91 (m, 2H), 7.03–7.12 (m, 3H), 7.25–7.36 (m, 5H); IR (KBr) 1755,
1618, 1512 cmꢀ1; MS (CI) m/z (rel intensity) 256 (MꢀClꢀ, 75), 161
(81), 106 (100). The NMR and IR data are in accord with data
published for the respective enantiomeric pure product.14
We thank Monika Simon for assistance in editing and
proofreading.
References and notes
1. (a) Crews, P.; Manes, L. V.; Boehler, M. Tetrahedron Lett. 1986, 27, 2797–2800; (b)
Roers, R.; Verdine, G. L. Tetrahedron Lett. 2001, 42, 3563–3565; (c) Namikoshi,
M.; Rinehart, K. L.; Dahlem, A. M.; Deasley, V. R. Tetrahedron Lett. 1989, 30,
4349–4352; (d) Shinagawa, S.; Kanamaru, T.; Harada, S.; Asai, M.; Okazaki, H. J.
Med. Chem. 1987, 30, 1458–1463; (e) Casiraghi, G.; Colombo, L.; Rassu, G.; Spanu,
P. J. Org. Chem. 1991, 56, 6523–6527.
2. (a) Zhao, X.; Hoesl, C.; Ho¨fner, G.; Wanner, K. T. Eur.J. Med.Chem. 2005, 40, 231–
247; (b) Kragler, A.; Ho¨fner, G.; Wanner, K. T. Eur. J. Pharmacol. 2005, 519, 43–47;
(c) Fu¨lep, G. H.; Hoesl, C. E.; Ho¨fner, G.; Wanner, K. T. Eur. J. Med. Chem. 2006,
41, 809–824; (d) Kragler, A.; Ho¨fner, G.; Wanner, K. T. Eur. J. Med. Chem., in
press.
4.4.20. (2RS,3SR)-3-Amino-2-methylbutyric acid hydrochloride
(7a$HCl)
NaIO4 (1.18 g, 5.52 mmol) was added to a solution of 13a
(150 mg, 1.20 mmol) in 9.1 mL H2O at rt and after stirring for 2 h,
aqueous NaOH (1.15 mL, 18.5 M) was added. After stirring for 24 h
at rt, the reaction mixture was neutralized with HCl (6 M) and
purified according to GP3 yielding the amino acid hydrochloride
7a$HCl (173 mg, 94%, ds>99:1, 1H NMR). The amino acid hydro-
chloride 7a$HCl was transformed to the corresponding free amino
acid using the acidic ion exchange resin Amberlite IR 120 for
comparison purpose with the published analytical data of the free
amino acid of 7a$HCl: mp 226–228 ꢁC; 1H NMR (500 MHz, D2O)
3. For reviews see: (a) Enantioselective Synthesis of b-Amino Acids; Juaristi, E., Ed.;
Wiley-VCH: New York, NY, 1997; (b) Liu, M.; Sibi, P. Tetrahedron 2002, 58, 7991–
8035; (c) Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1–15; (d) Juaristi, E.;
Lo´ pez-Ruiz, H. Curr. Med. Chem. 1999, 6, 983–1004.
4. Ege, M.; Wanner, K. T. Org. Lett. 2004, 6, 3553–3556.
d
1.19 (d, J¼7.3 Hz, 3H), 1.29–132 (m, J¼6.7 Hz, 3H), 2.50–2.52 (m,
5. (a) Al-awar, R. S.; Joseph, S. P.; Comins, D. L. J. Org. Chem. 1993, 58, 7732–7739;
(b) Kuethe, J. T.; Wong, A.; Davies, I. W.; Reider, P. J. Tetrahedron Lett. 2002, 43,
3871–3874.
1H), 3.46–3.49 (m, 1H); IR (KBr) 1723, 1633, 1470, 1206 cmꢀ1; MS
(CI) m/z (rel intensity) 118 (MHþ, 100). The NMR and IR data are in
accord with data published for the respective enantiomeric pure
product.20
6. (a) Krause, N. Angew. Chem. 1994, 106, 1845–1847; (b) Krause, N.; Ebert, S.;
Haubrich, A. Liebigs Ann. 1997, 2409–2418; (c) Bordwell, F. G. Acc. Chem. Res.
1988, 21, 456–463; (d) Eigen, M. Angew. Chem. 1963, 75, 489–508; (e) Eigen, M.
Angew. Chem. 1968, 80, 892–906; (f) Johnson, F. Chem. Rev. 1968, 68, 375–413.
7. (a) Hoesl, C. E.; Maurus, M.; Pabel, J.; Polborn, K.; Wanner, K. T. Tetrahedron
2002, 58, 6757–6770; (b) Comins, D. L. J. Heterocycl. Chem. 1999, 36, 1491–1500;
(c) Streith, J.; Boiron, A.; Sifferlen, T.; Strehler, C.; Tschamber, T. Tetrahedron Lett.
1994, 35, 3927–3930.
4.4.21. (2RS,3RS)-3-Amino-2-benzyl-3-phenylpropionic acid
hydrochloride (7b$HCl)
NaIO4 (223 mg, 1.08 mmol) was added to a solution of 13b
(60 mg, 0.22 mmol) in 1.5 mL H2O and 1.5 mL THF at rt. After stir-
ring for 65 h, NaOH (0.65 mL, 16.9 M) was added and the reaction
mixture was subsequently stirred for another 65 h at rt. The re-
action mixture was neutralized with HCl (6 M) and adsorbed on an
acidic ion exchange resin (Amberlite IR 120). The resin was washed
with distilled water until the washings were neutral and the free
amino acid was eluted with aqueous NH3 (20%). The eluate was
concentrated, dissolved in HCl (1 M), and washed with EtOAc (5ꢂ).
The aqueous solution was neutralized and adsorbed on a basic ion
exchange resin (Amberlite IR 410). The resin was first washed with
distilled water until the washings were neutral, and then eluted
with HCl (2 M). Following evaporation, the amino acid hydrochlo-
rides 7b$HCl and 6a$HCl were obtained in a ratio of 95:5 (1H NMR)
(31 mg, 61% referring to 7b$HCl and 6a$HCl) as colorless solid
(31 mg, 61%, ds¼95:5, 1H NMR): mp 230–233 ꢁC (lit. mp21
8. (a) Comins, D. L.; Zhang, Y.-M.; Joseph, S. P. Org. Lett. 1999, 1, 657–659; (b)
Comins, D. L.; LaMunyon, D. H.; Chen, X. J. Org. Chem. 1997, 62, 8182–8187.
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Shing, T. M. K.; Gang, Y. Tetrahedron 1990, 46, 2187–2194.
10. Alkahatlan, H. Z. Synth. Commun. 1992, 22, 2659–2671.
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Chemie; Thieme: Stuttgart, 1991; pp 106–109.
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16. Estermann, H.; Seebach, D. Helv. Chim. Acta 1988, 71, 1824–1839.
17. Davies, S. G.; Ichihara, O.; Walters, I. S. J. Chem. Soc., Perkin Trans. 1 1994,
1141–1147.
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21. Moriconi, E. J.; Kelly, J. F. J. Org. Chem. 1968, 33, 3036–3046.