Asymmetric steering of the Mannich reaction with phthaloyl amino acids

Article abstract of DOI:10.1002/1521-3765(20000602)6:11<2032::AID-CHEM2032>3.0.CO;2-B

Mannich-type reactions are powerful methods for the efficient synthesis of β-amino carbonyl compounds that are valuable intermediates for the construction of natural products, β-peptides, and peptidomimetics. For the efficient steric steering of Mannich r

Full text of DOI:10.1002/1521-3765(20000602)6:11<2032::AID-CHEM2032>3.0.CO;2-B

FULL PAPER
Asymmetric Steering of the Mannich Reaction with Phthaloyl Amino Acids
Roland Müller,[b] Herbert Röttele,[b] Henning Henke,[c] and Herbert Waldmann*[a]
Abstract: Mannich-type reactions are
powerful methods for the efficient syn-
thesis of b-amino carbonyl compounds
that are valuable intermediates for the
construction of natural products, b-pep-
tides, and peptidomimetics. For the effi-
cient steric steering of Mannich reac-
tions a method was developed that
consists in the treatment of imines with
N-protected amino acid chlorides to give
N-acyliminiumion intermediates that
are subsequently attacked with silylke-
tene acetals. The reactions are run best
at room temperature and in the absence
of any Lewis acid. The highest stereo-
selectivity is observed if N,N-phthaloyl
tert-leucine is employed as chiral auxil-
iary and if N-aryl,C-aryl Schiffs bases
are used that carry two ortho-substitu-
ents in either aromatic ring. Under these
conditions the Mannich adducts are
formed in preparatively useful yields
and with excellent stereoselectivity (di-
astereomer ratio in general >99:1). The
chiral auxiliary group is readily removed
by 1) cleavage of the phthaloyl imide via
reduction with NaBH4 and acid hydro-
lysis followed by 2) Edman degradation.
Keywords: amino acids ´ asymmet-
ric synthesis ´ b-amino acids ´ chiral
auxiliaries ´ Mannich reaction
A particularly efficient transformation that can be em-
ployed to achieve this goal is the Mannich reaction. Con-
sequently, the development of diastereo- and enantioselective
Mannich reactions has been the focus of numerous research
enterprises.[3] However, unlike the development of for exam-
ple asymmetric aldol reactions, these investigations have met
with only limited success. In general, in these transformations
either a chiral nucleophile or electrophile was employed to
steer the steric course of the reaction, or chirality was
introduced by activation of an imine with a chiral Lewis acid.
However, in an alternative variant of the Mannich reaction a
Schiff base is activated by treatment with an acid chloride
giving rise to an N-acyliminium intermediate which then is
attacked by the nucleophile, for example a silylketene
acetal.[4] Thus, the use of chiral acid chlorides in this trans-
formation opens up alternative opportunities for the develop-
ment of asymmetric Mannich-type reactions. We have re-
cently shown that N-acyliminium intermediates generated in
situ from N-protected amino acid chlorides and indolylethyl
imines undergo highly stereoselective Pictet ± Spengler reac-
tions.[5] In this paper we report in full detail on the develop-
ment of amino acid derived acid chlorides as efficient
mediators of chirality in Mannich-type processes.[6]
Introduction
Numerous biologically active natural products embody the b-
aminocarbonyl substructure and biological activity often is
associated with the absolute configuration of this structural
subunit.[1] For instance, the tumor-suppressing drug Taxol
carries phenylisoserine as side chain, and the antitumor
activity of the natural product is correlated with the correct
absolute configuration of this b-amino acid.[2c,d] In addition, b-
amino acids have recently gained increasing interest as
building blocks for b-peptides, a class of novel and promising
peptide analogues.[2a,b] Furthermore, enantiomerically pure b-
aminocarbonyl compounds are valuable intermediates and
reagents for the construction of natural products and ana-
logues thereof. Due to this importance, the development of
efficient methods for the synthesis of enantiomerically pure b-
aminocarbonyl compounds is of great importance to organic
synthesis.
[a] Prof. Dr. H. Waldmann
Max-Planck-Institut für Molekulare Physiologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
and
Universität Dortmund, FB 3, Organische Chemie
Fax : (‡49)231-1332699
E-mail: waldmann@mpi-dortmund.mpg.de
[b] Dr. R. Müller, Dr. H. Röttele
Institut für Organische Chemie der Universität Karlsruhe
Richard-Willstätter-Allee 2
Results
76128 Karlsruhe (Germany)
[c] Dr. H. Henke
Treatment of Schiff bases with acid chlorides leads to rapid
formation of a-chloroalkylamides, from which N-acyliminium
ions are generated by means of Lewis acids.[7] Therefore, in a
Institut für Anorganische Chemie der Universität Karlsruhe
Richard-Willstätter-Allee 2
76128 Karlsruhe (Germany)
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Chem. Eur. J. 2000, 6, No. 11

2032±2043
first series of experiments the influence of Lewis acids, the size
of the amino acid side chain and the protecting group on the
reaction between Schiffs base 1, acid chlorides 2, and
silylketene acetal 3 were investigated (Scheme 1, Table 1). If
temperature, lowering the temperature led to a decrease in
yield but not to an increase in stereoselectivity.
a-Chloroalkylamides and N-acyliminium ions are in equi-
librium with each other. The position of the equilibrium and
the reactivity of the iminium ions are strongly influenced by
the substituents of the imine.[7] Therefore, the N- and the C-
substituents of the Schiff bases were varied in a second series
of experiments. If imines 6 with two aromatic substituents
were treated with N,N-phthaloyl tert-leucine chloride (2b)
and silylketene acetals 3 or 7 the desired Mannich adducts 8
and 9 were formed in moderate to high yield and with high to
excellent diastereomer ratio in the majority of the cases
(Scheme 2, Table 2). The highest yields were recorded if the
O
Ph
N
NPG
+
Cl
Ph
R
1
2a-d
O
NPG
O
R1
N
O
R3
R3
OSiMe3
OR4
R
N
N
+
+
Cl
O
R2
Cl
3 (R3 = CH3) or
7 (R3 = H, R4 = Et)
OSiMe3
OMe
6a-l
2b
Lewis acid
CH2Cl2
rt
72 h
3
i, ii
O
O
NPG
NPG
N
O
N
O
O
O
R1
R2
R1
R
R
+
NPht
NPht
N
N
O
+
OCH3
tBu
OR4
tBu
OMe
R2
5a-d
4a-d
O
OR4
Scheme 1. Asymmetric Mannich reactions via N-acyliminium intermedi-
ates employing different N-protected amino acids as chiral auxiliaries.
8a-o
9a-o
Scheme 2. Asymmetric steering of the Mannich reaction with N,N-
phthaloyl tert-leucine as chiral auxiliary. i) CH2Cl2, rt, 72 h; ii) 10% aq.
NaHCO3.
Table 1. Results of the Mannich reactions between imine 1, N-protected
amino acid chlorides 2 and silylketene acetal 3.
Table 2. Results of the Mannich reactions employing imines 6, N,N-
phthaloyl tert-leucine chloride (2b) and silylketene acetals 3 and 7.
Entry
2
R
PG[a]
t [h]
Yield [%]
dr[b]
4/5
1
2
3
4
5
6
a
a
a
b
c
iPr
iPr
iPr
tBu
(CH2)3
iPr
Pht
Pht
Pht
Pht
Z
22
73
20
72
72
72
17[c]
13[d]
80
54
69
90:10
90:10
87:13
93:7
53:47
±
a
a
a
b
c
Entry R1
R2
6
Nu Yield [%] dr[a]
8/9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H
H
H
H
H
4-NO2
4-OMe
2-OMe-6-Me
H
2-OMe-6-Me 4-Cl
2-OMe-6-Me 2-OMe
2-OMe-6-Me 4-OMe
2-OMe-6-Me
2-OMe-6-Me 4-OMe
2-OMe-6-Me 2-OMe
3-NO2
4-Cl
2,4,6-Me3
4-NMe2
4-OMe
H
H
H
2-OMe
a
b
c
d
e
f
g
h
i
j
k
l
h
l
k
3
3
3
3
3
3
3
3
3
3
3
3
7
7
7
±
44
46
81
84
±
82
50
91
13
59
75
34
51
68
±
92:8
> 99:1
91:9
91:9
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
d
Fmoc
±
d
[a] PG ˆ Protective group. [b] Determined by HPLC from the crude
reaction mixture. [c] 1 equiv BF3 ´ OEt2 was used as Lewis acid.
[d] 0.05 equiv BF3 ´ OEt2 were used as Lewis acid.
±
91:9
> 99:1
92:8
> 99:1
> 99:1
> 99:1
97:3
Lewis acids such as SnCl4, TiCl4, BCl3, ZnCl2, or BF3 ´ OEt2
were employed and N,N-phthaloyl valine chloride was used,
in the majority of the cases the desired b-amino acid esters 4
and 5 could not be detected. The products were formed in 13 ±
17% with a diastereomer ratio of 90:10 only in the presence of
BF3 ´ OEt2 (Table 1, entries 1 and 2). In the absence of any
Lewis acid, however, the b-aminocarbonyl compounds 4 and 5
were obtained in 80% yield and with a diastereomer ratio of
87:13 (Table 1, entry 3). Increasing the size of the amino acid
side chain led to a significant enhancement of the stereo-
selectivity, but also to a decrease in yield (Table 1, entries 3
and 4). The use of proline resulted in decreased stereo-
selectivity and application of a different N-protecting group
gave inferior results as well (Table 1, entries 5 and 6). Notably,
the best results were obtained by running the reaction at room
H
> 99:1
> 99:1
[a] Determined by HPLC from the crude reaction mixture.
aromatic rings carried electron-donating substituents. If either
one of the aromatic ring was nitro-substitued the Mannich
products were not formed (Table 2, entries 1 and 6). If the
aromatic rings carried only one substituent either in the ortho-
or the para-position, diastereomer ratios of 91:9 ! 92:8 were
determined (Table 2, entries 2, 4, 5, 7, and 9). If, however,
either one of the two aryl rings carried two ortho-substituents
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H. Waldmann et al.
FULL PAPER
Table 3. Results of the Mannich reactions employing imine 6c, N,N-
phthaloyl tert-leucine chloride (2b) and silylketene acetals 10 ± 12.
the isomer ratio was >99:1 (Table 2, entries 3, 8, 10 ± 12, 14,
and 15; for entry 13, a somewhat lower selectivity was
determined). Treatment of N-alkyl,C-aryl imines or N-aryl,C-
alkyl imines with acid chloride 2b and silylketene acetal 3, in
general, did not lead to Mannich products 8 and 9. Only the
imine formed from benzylamine and benzaldehyde gave b-
amino acid esters isolated in 27% yield with an isomer ratio of
83:17. In all other cases N-protected amino acid amides were
isolated resulting from hydrolysis of the intermediary formed
iminium ions.
The substituents at the a-position of the silylketene acetals
were varied in a third series of experiments. Replacement of
dimethyl-substituted nucleophile 3 (Scheme 2, R3 ˆ CH3) by
methylene silylketene acetal 7 (Scheme 2, R3 ˆ H) influenced
yield and selectivity of the asymmetric transformation only to
a minor extent (Table 2, compare entries 8, 11, and 12 with
entries 13 ± 15). In the case of Mannich adducts 8n and 8o
only one diastereomer could be detected. In the reactions
between imine 6c, acid chloride 2b, and silylketene acetals
10 ± 12, four diastereomers can be formed in each case since
two new stereogenic centres are generated (Scheme 3,
Entry
Silylketene acetal
Product
Yield [%]
syn/anti[a]
1
2
3
10
11
12
13
14
15
78
77
66
61:39
83:17
> 99:1
[a] Determined by HPLC from the crude reaction mixture.
was (S)-configured. Thus, the silylketene acetal must have
attacked the Re-face of the imine double bond (see the
Discussion and Scheme 9). The configuration of the second
stereogenic centre in compounds 13, 14, and 15 was assigned
based on analysis of NOESY spectra recorded for compounds
13syn (major diastereomer) and 13anti (minor diastereomer)
and on the assumption that these nucleophiles attack the
imines predominantly from the Re-face as well. Both diaster-
eomers showed a set of common NOE signal enhancements
between an ortho-H of the N-aryl substituent and 2-H,
between 2-H and 3-Hb as well as 2H and an ortho-CH3 of the
mesityl substituent, 3-Ha and b-H, and between b-H and the
other ortho-CH3a (Scheme 4). However, in the major diaster-
OTMS
O
PhtN
O
PhtN
O
R*
R*
6c
+
10
+
NPh
NPh
O
O
2b
O
N
O
N
O
O
O
H
Ha
b
H
CHb3
H
CHb3
H
H
1
3
2
Hβ
CHa3
2
Hβ
CHa3
O
H
13 syn
13 anti
H
4
Hb
Ha
3
1
4
H
MeO
OTMS
OMe
O
H3C
PhtN
O
PhtN
O
H3C
O
H
6c
+
2b
11
16
17
+
OMe
NPh O
OMe
NPh O
OMe
Scheme 4. Determination of the relative configuration of Mannich ad-
ducts 13syn (ˆ16) and 13anti (ˆ17) by means of NOE measurements.
OMe
14 syn
14 anti
eomer 16 (13syn) additional characteristic NOE signal
enhancements between an ortho-H of the N-aryl substituent
and 3-Ha as well as 3-Hb were detected. In the minor
diastereomer 17 (13anti) the 3-CH2-group and the ortho-
positions of the N-aryl ring are not in close poximity. The
specific pattern of NOEs can be explained by the conforma-
tions and absolute configurations of 16 for the major
diastereomer and 17 for the minor diastereomer. Thus, in
the Mannich reaction with the cyclic silylketene acetal syn
diastereomer 13syn was predominantly formed. The relative
configuration of the diastereomers 14syn/anti and 15syn were
assigned based on the assumption that for all three a-
substituted silylketene acetals similar transition states are
passed (see the Discussion and Scheme 9).
Removal of the chiral auxiliary group was achieved in a
two-step procedure. Reduction of the phthaloyl group present
in compounds 8c, 8g, 8h and subsequent hydrolysis with
dilute HCl[10] yielded N-terminally deprotected tert-leucine
amides 18a, 18c, and 18/19b (synthesized as a 92:8 mixture of
diastereomers 18b and 19b; Scheme 5, Table 4). From these
amino acid amides tert-leucine was cleaved by Edman
degradation with phenylisothiocyanate and hydrolysis in
OTMS
OMe
PhtN
O
TBSO
6c
+
2b
12
NPh O
OMe
OTBS
15 syn
Scheme 3. Asymmetric Mannich reactions with a-monosubstitued silylke-
tene acetals.
Table 3). In all three cases, the face selectivity of the imine was
complete. For (E)-substitued cyclic ketene acetal 10, the two
possible syn/anti isomers 13syn and 13anti were formed in a
ratio of 61:39. (Z)-Configured silylketene acetal 11 gave syn/
anti isomers 14syn and 14anti in a ratio of 83:17, and (Z)-
OTBSsilylketene acetal 12 yielded exclusively syn isomer
15syn.
The absolute configuration of the stereogenic centre in the
benzylic position was determined by X-ray analysis. The a-C
of the tert-leucine auxiliary served as reference. Analysis of
compounds 8c[9] and 8h[9] revealed that the stereogenic centre
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Mannich Reaction
2032±2043
O
R1
R1
R2
LA
R
O
R
H
O
O
NH2
LA
Ar1
Ar2
Ar1
Ar2
i
8c,g,h
R2
ii
N
O
NH
O
Ar1
Ar2
N
N
R
N
tBu
OCH3
Cl
Cl
OCH3
23
24
25
LA = Lewis acid
20a,c or 20b/21b
18a,c or 18b/19b
Scheme 7. Possible reaction of intermediary formed a-chloralkyl amides
with Lewis acids.
Scheme 5. Cleavage of the phthaloyl groups from Mannich adducts 8c, g,
h. i) 1) 5 equiv NaBH4, iPrOH/H2O 7:1, rt, 2) 18 equiv conc. HCl, 808C;
ii) 1) 2 equiv PhNCS, 1 equiv NaOH (0.2m), pyridine/H2O 1:1, rt, 3 h,
2) 20% TFA in CH2Cl2, reflux.
that the Lewis acid does not only activate the electrophile, but
that it also may activate the silylketene acetal. In this case a
low concentration of the Lewis acid would result in a
decreased reaction rate.
Table 4. Results of the removal of the chiral auxiliary groups from the
Mannich adducts.
The efficiency of the stereoselection is influenced by the
size of the amino acid side chain and the nature of the
protecting group. Thus, tert-leucine gives a significantly higher
diastereomer ratio than valine. Use of the cyclic amino acid
proline which had proven to be a more advantageous auxiliary
in other asymmetric syntheses[17] led to nearly equal amounts
of the two diastereomers. Since tert-leucine is the most bulky
of the commercially readily available amino acids it was used
in all further Mannich reactions. If the phthalide is replaced by
an urethane, the Mannich adducts are not formed at all. A
similar behavior was observed in the application on N-masked
amino acid chlorides as mediators of chirality in Pictet ±
Spengler reactions with indolylethylamines.[5] Therefore, we
have not investigated further N-blocking groups in the
Mannich-type transformations and used the phthaloyl pro-
tecting group in all further experiments.
Entry R1
R2
8
Yield [%] 18 Yield[%] 19
1
2
3
H
2,4,6-Me3
H
H
c
g
h
88
97
65
a
b
c
59
84
45
a
b
c
4-OMe
2-OMe-6-Me
20% trifluoroacetic acid[12] to give N-aryl b-amino acid esters
20a, 20c, and 20b/21b (Scheme 5, Table 4). All attempts to
remove the chiral auxiliary by hydrolysis under basic or acidic
conditions failed, e. g. by hydrolysis in concentrated mineral
acids, by treatment with peroxide anions[13], with KOtBu[14] or
by O-alkylation of the amide group with Meerweinꢁs salt and
subsequent aqueous hydrolysis. From compound 20c the
ortho-methoxy substituted N-aryl group was removed by
oxidation with cerium ammonium nitrate (CAN).[16] b-Amino
acid methyl ester hydrochloride 22 was obtained in 56% yield
(Scheme 6).
The type of the substituent linked to the imine carbon and/
or nitrogen and its electronic properties determine whether
the Mannich adducts are formed or not. Thus, if either one of
the two substituents is aliphatic and the other one is aromatic,
the reaction does not proceed. Also, the desired products are
not formed, if two aromatic substituents are present and one
of them carries an electron-withdrawing nitro group. On the
contrary, the Mannich adducts are obtained in preparatively
useful yields if at least one of the two aryl substituents is
equipped with an electron-donating functional group, in
particular a methoxy function. We assume that the Mannich
reactions only proceed smoothly if the acyliminium inter-
mediates are stabilised by an electron-donating group that
partially delocalises the positive charge. Also, an aromatic
substituent next to the a-chloroamide may favor the elimi-
nation of the chloride by neighboring-group assistance.[18] This
effect should be particularly pronounced in the presence of
‡M substituents.
OCH3
NH
Cl
NH3
O
O
i, ii
OCH3
Ph
OCH3
20c
22
[α]22D = +34.7
(c = 0.205, 1 M HCl)
Scheme 6. Oxidative cleavage of the N-aryl substituent from b-amino acid
20c. i) 5 equiv CAN, 08C to 228C; ii) Et2O, 56% HCl.
Discussion
The results given in Table 1 clearly demonstrate that the
Mannich reactions studied here are best carried out in the
absence of any Lewis acid. Although in the presence of BF3 ´
OEt2 the stereoselectivity is somewhat higher, under these
conditions the yield is not in the preparatively useful range
(Table 1, compare entries 1 ± 3). A possible explanation is that
the a-chloroalkylamides 23 formed from the imines and the
acid chlorides may react with the Lewis acid to give imidates
24 which can not be converted to the reactive N-acyliminium
ions 25 (Scheme 7). This would explain the result recorded in
the presence of 1 equiv BF3 ´ OEt2; it does, however, not
account for the fact that in the presence of 5 mol% of this
Lewis acid the yield is even lower (Table 1, entries 1 and 2).
This low yield may be rationalised based on the assumption
The efficiency of the stereoselection is decisively influenced
by the substitution pattern of the N- or C-aryl group. If either
one of the two aromatic groups is monosubstituted the isomer
ratio consistently is between 91:9 and 92:8, irrespective of the
precise nature and the position of the substituent (Table 2,
entries 2, 4, 5, 7, and 9). However, if in the imine either the
former aniline aryl group or the former aromatic aldehyde
embodies two ortho-substituents the diastereomer ratio
increases dramatically. In nearly all cases investigated with
a-disubstituted silylketene acetals 3 and 7 only one diaster-
eomer could be detected by HPLC and NMR (Table 2, entries
3, 8, and 10 ± 15).
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H. Waldmann et al.
FULL PAPER
This extremely high selectivity for stereogenic centre at the
benzylic carbon atom corresponding to the former imine C is
also observed if silylketene acetals are employed that carry
one substituent in the a-position. In these cases four diaste-
reomers may be formed, that is two syn- and two anti isomers.
However, in all three cases examined, only one syn- and one
anti diastereomer were detected. Thus, in these cases, too, the
imine was only attacked from one of its diastereotopic faces.
The syn/anti selectivity depends on the steric demand of the
substituent in the a-position of the nucleophile. Thus, with
increasing size of the a-substituent (from CH2 via OCH3 to
OTBS) the diastereomer ratio increases (Table 3) independ-
ently whether an (E)- or an (Z)-silylketene acetal is employed.
In all cases the reaction with the silylketene acetals 10, 11, and
12 gave predominantly or exclusively syn diastereomers.
The chiral auxiliary group can be removed from the
Mannich adducts by means of a straightforward two-step
procedure. In the first step one of the carbonyl groups of the
phthalide is reduced to the alcohol, which readily hydrolyses
the remaining amide in the presence of diluted HCl. The
resulting amino acid amide is then cleaved by means of
Edman degradation. All attempts to cleave the tert-leucine
amide directly under strongly acidic or basic conditions or by
means of a supernucleophile completely failed. The amino
O
Ar1
H
N
NPht
+
Cl
Ar2
tBu
2b
26
O
Ar2
O
Ar1
H
NPht
NPht
N
H
N
Ar1
tBu
tBu
Ar2
27a
27b
O
O
O
N
Ar1
H
NPht
Ar1
NPht
Ar1
Cl
NPht
N
N
tBu
tBu
tBu
Ar2
Ar2
Cl
H
Ar2
Cl
H
28a
28b
28c
+ Cl
- Cl
O
Ar1
NPht
N
tBu
Ar2
H
ˆ
acid C O group is surrounded by bulky groups and obviously
29
no longer accessible for an externally approaching nucleo-
phile. However, if the nucleophile is generated intramolecu-
larly, as is the case in the Edman degradation, attack on the
tertiary amide becomes possible and the bond between the
chiral auxiliary and the b-amino acid ester is cleaved
smoothly.
The presence of an ortho-methoxy substituent in the N-aryl
group does not only guarantee high yields and excellent
stereoselectivity. It also provides an opportunity for the
removal of the aryl group. Thus, upon treatment of 20c with
cerium ammonium nitrate the N-aryl bond was cleaved
oxidatively and the desired b-amino acid ester 22 was
obtained in good yield as the corresponding hydrochloride.
The specific rotation recorded for this compound was in good
agreement with literature data[3g, 3m] and indicated that the
(R)-enantiomer had been formed.
OCH3
OTMS
O
Ar1
NPht
N
O
tBu
Ar2
OCH3
30
ˆ
Scheme 8. Proposed intermediates and (E) ± (Z)-isomerisation of the C N
bond in the Mannich reaction with N,N-phthaloyl tert-leucine chloride.
tBu
tBu
PhtN
PhtN
R
H
H
H
O
H
O
N
N
R
However, determination of the absolute configuration of
Mannich adducts 8c and 8h by X-ray crystallography clearly
and unambiguously had proven that the configuration of the
newly formed stereogenic centre was (S).[9] Since the data
reported in the literature were based on an assignment of the
absolute configuration by chemical correlation (see[3g] and[3m]
and the references therein) but not on X-ray analysis, we
suggest that the published assignments of the absolute
configuration of 22 should be revised.
R´
A
R
R´
B
R
tBu
PhtN
H
O
H
R´
N
R
In order to rationalise the excellent stereoselectivity
recorded for the Mannich reactions we propose that the
transformations proceed by the mechanism shown in
Scheme 8 and via the transition states shown in Schemes 9
and 10. The Schiff bases 26 react with N,N-phthaloyl tert-
leucine chloride (2b) to form (Z) ± trans acyliminium salts 27.
Chloride then adds anti to the tert-butyl group of 27a to the
R´
C
Scheme 9. Proposed tilting of aromatic rings in the N-acyliminium
intermediates due to unfavored steric interactions.
acid side chain. This unfavorable steric interaction is relieved
ˆ
À
C N double bond yielding a-chloromethyl amide 28a. In 27a
by rotation around the C N single bond. Thereby, conformers
28a are converted into conformers 28b which eliminate
and 28a the Ar2 group is in close proximity to the bulky amino
2036
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0947-6539/00/0611-2036 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 11

Mannich Reaction
2032±2043
chloride to yield (E) ± trans iminium intermediates 29. The
leading to syn isomers. In A and B unfavorable interactions
between a-substituents R1 and the tilted aromatic ring have to
be expected. In A substituent R1 is in proximity to the two aryl
groups of the imine. Transition states C leading to syn isomers
for 10 and 12 appear to determine the steric course of the
transformations. Obviously the interactions between the
bulky R1 and the aryl group of the imine in transition state
A are more severe than the interactions of the OTMSgroup
with the tilted aromatic ring. For the same reason, the use of
the (Z)-silylketene acetal 11 leads to predominant formation
of the syn diastereomer via transition state D. Thus, the
orientation of R1 and not the silyl group relative to the N-
acyliminium ion is the decisive factor.
ˆ
silylketene acetals then attack the C N double bond of 29
from the face opposite to the bulky amino acid side chain. This
explains the increase of the stereoselectivity with increasing
steric demand of the amino acid side chain.
The imine carbon is converted into a stereocenter with (S)-
ˆ
configuation, thus the C N bond must have been attacked
from the Re-face. This is the case if the nucleophile
approaches intermediate 29 anti to the tert-butyl group.
Alternatively, a Re-face attack anti to the amino acid side
chain would be possible if (Z) ± cis rotamer 27b would be the
decisive intermediate (Scheme 8). However, in 27b the aryl
ring Ar1 is unfavorably close to the tert-butyl group of the
2
ˆ
amino acid, and Ar points towards the C O group. Thus 27b
is higher in energy than 27a.
In (E)-trans conformation 29 the ortho-substituents of the
two adjacent phenyl groups can point directly towards each
other giving rise to disturbing steric interactions (Scheme 9,
A). These can be compensated by tilting one aryl group out of
Conclusion
We have developed a method for the steric steering of the
Mannich reaction via N-acyliminium intermediates. The best
chiral auxiliary, N,N-phthaloyl tert-leucine, is readily available
in both enantiomeric forms and the asymmetric transforma-
tions are easily carried out. In particular, a Lewis acid is not
needed and the reactions are run best at room temperature.
The Mannich adducts are obtained in acceptable to high
yields and with excellent diastereomer ratios. The chiral
auxiliary group is readily removed via a simple two-step
process. By means of this method various b-amino acids are
available that can find numerous applications, for example in
the synthesis of b-peptides, peptidomimetics, and natural
products.
ˆ
the plane of the C N bond (Scheme 9, B and C). This effect
should be particularly pronounced if either one of the two aryl
groups embodies ortho-substituents. One ortho-substituent of
the tilted ring would additionally shield the sterically less
ˆ
accessible face of the C N bond and thereby enhance the
stereodiscrimination. This proposal accounts for the observa-
tion that the stereoslectivity dramatically increases if one of
the two aryl groups of the imine is di-ortho-substituted.
In order to explain the stereoselectivity for the reactions
with the silylketene acetals carrying only one substituent at
ˆ
the a-carbon, we assume that they also attack the C N bond
at the face opposite to the amino acid side chain (Scheme 10).
In this case for (E)-silylketene acetals 10 and 12 transition
state C shown in Scheme 10 may be passed predominantly,
Experimental Section
General procedures: Melting points were determined in open capillaries
using a Büchi 535 apparatus and are uncorrected. 1H- and 13C-NMR spectra
were recorded on a Bruker AC250, AM400, or DRX500 spectrometer at
O
H
O
H
Ar1
NPht
Ar1
NPht
N
N
room temperature. IR spectra were recorded on
a Bruker IFS88
tBu
tBu
spectrometer. Mass spectra and high-resolution mass spectra (HR-MS)
were measured on a Finnigan MAT MS70 spectrometer. Elementary
analyses were performed on a Heraeus CHN-Rapid apparatus. HPLC was
performed on a Spherisorb ODS II 250/4/5 analytical column (Bischoff)
and methanol/water as eluent at a flow rate of 0.6 mLminÀ1 and on a
LiChrosorb RP-18 250/25/7 semipreparative column (MERCK).
R1
R1
R2O
OTMS
O
TMSO
OR2
O
A
B
Materials: Solvents were dried by standard methods and stored over
molecular sieves. Deuterochloroform was carefully degassed prior to use by
three times freezing under argon atmosphere and warming up under
reduced pressure. For column chromatography silica gel (40 ± 60 mm,
Baker) was used. Commercial reagents were used without further
purification. Where indicated the reactions were performed under nitrogen
or argon. Several compounds were prepared according to literature
methods: N-phenyl-3-nitrobenzylidene amine (6a);[20] N-phenyl-4-chloro-
benzylidene amine (6b);[21] N-phenyl-2,4,6-trimethylbenzylidene amine
(6c);[21] N-phenyl-4-dimethylaminobenzylidene amine (6d);[22] N-phenyl-4-
methoxybenzylidene amine (6e);[20] N-(4-nitrophenyl)-benzylidene amine
(6 f);[21] N-(4-methoxyphenyl)-benzylidene amine (6g);[21] N-phenyl-2-
methoxybenzylidene amine (6i);[23] N,N-phthaloyl valine chloride (2a);[24]
N,N-pthaloyl tert-leucine chloride (2b);[24] Z-proline chloride (2c);[25]
Fmoc-valine chloride (2d);[26] 1-ethoxy-1-trimethylsiloxy-ethene (7);[27]
3,4-dihydro-1-trimethylsiloxy-furan (10);[28] (Z)-1,2-dimethoxy-1-trime-
thylsiloxy-ethene (11);[29] (E)-2-(dimethyl-tert-butyl)-siloxy-1-methoxy-1-
trimethylsiloxy-ethene (12).[1g]
Ar1
NPht
Ar1
NPht
N
N
tBu
tBu
H
H
R1
R1
TMSO
OR2
R2O
Aux
OTMS
C
D
Ar1
H
Aux
N
Ar1
H
Ar1
Ph
Aux
Ar1
N
Aux
COOR2
N
N
R1
H
R1
COOR2
Ph
Ph
O
Ph
R2O
H
R1
R1
OR2
O
syn
syn
Scheme 10. Proposed transition states for the reactions between the N-
acyliminium intermediates with (E)- and (Z)-silylketene acetals.
Preparation of N-(2-methoxy-6-methylphenyl)-benzylidene amines (6h,
6j ± k). General procedure: A neat mixture of 2-methoxy-6-methylaniline
Chem. Eur. J. 2000, 6, No. 11
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2037

H. Waldmann et al.
FULL PAPER
(1.38 g, 10 mmol) and the corresponding aldehyde (10 mmol) was heated at
808C for several hours. The resulting red oil was dissolved in diethyl ether
(10 mL) and washed with acetic acid (5% aqueous). The combined organic
layers were dried over K2CO3 and concentrated under reduced pressure.
(methanol/H2O 62:38); 1H NMR (250 MHz, CDCl3): d ˆ 7.64 (s, 4H), 7.36 ±
7.44 (m, 2H), 7.11 ± 7.26 (m, 6H), 6.57 (dd, J ˆ 8, 7 Hz, 1H), 6.19 (s, 1H),
5.80 (d, J ˆ 8 Hz, 1H), 4.38 (d, J ˆ 10 Hz, 1H), 3.63 (s, 3H), 2.85 (dqq, J ˆ 7,
7, 10 Hz, 1H), 1.35 (s, 3H), 1.22 (s, 3H), 1.11 (d, J ˆ 7 Hz, 3H), 0.71 (d, J ˆ
7 Hz, 3H); MS(70 eV, EI): m/z (%): 512 (2), 481 (2), 411 (35), 282 (4), 230
(14), 202 (100); C31H32N2O5 (512.60): calcd C 72.64, H 6.29, N 5.47; found: C
N-(2-Methoxy-4-methylphenyl)-benzylidene amine (6h): The product was
obtained as a yellow solid after recrystallization from ethanol (85%
aqueous). Yield: 50%; m.p.: 478C; 1H NMR (400 MHz, CDCl3): d ˆ 8.40
(s, 1H), 7.92 (dd, J ˆ 5, 5 Hz, 2H), 7.47 (d, J ˆ 5 Hz, 1H), 7.47 (dd, J ˆ 2,
5 Hz, 2H), 6.99 (dd, J ˆ 8, 8 Hz, 1H), 6.84 (d, J ˆ 8 Hz, 1H), 6.82 (d, J ˆ
8 Hz, 1H), 3.75 (s, 3H), 2.23 (s, 3H); 13C NMR (125.8 MHz, CDCl3): d ˆ
163.91 (CH), 149.54 (q), 140.54 (q), 136.51 (q), 131.19 (CH), 131.12 (q),
128.62 (CH), 128.57 (CH), 124.37 (CH), 122.64 (CH), 109.52 (CH), 55.86
(CH3), 18.09 (CH3); MS(70 eV, EI): m/z (%): 225 (100), 210 (27), 194 (7),
148 (20), 104 (11), 91 (11), 77 (15); C15H15NO (225.29): calcd C 79.97, H
6.71, N 6.22; found: C 80.00, H 6.69, N 6.11; HR-MS(70 eV, EI): m/z: calcd
‡
72.56, H 6.29, N 5.50; HR-MS(70 eV, EI): m/z: calcd for [M] : 512.2311,
found: 512.2322.
Methyl 2,2-dimethyl-(S)-3-phenyl-3-[N-phenyl-N-((S)-N',N'-phthaloylval-
yl)]-amino-propionate (5a): Characteristic analytical data for the minor
product. HPLC: tR ˆ 92'25'' (methanol/H2O 62:38); 1H NMR (250 MHz,
CDCl3): d ˆ 5.88(s, 1H), 4.24 (d, J ˆ 10 Hz, 1H), 3.61 (s, 3H).
Methyl
2,2-dimethyl-(S)-3-phenyl-3-[N-phenyl-N-((S)-N',N'-phthaloyl-
tert-leucyl)]-amino-propionate (4b): The products were obtained from
N,N-phthaloyl-tert-leucylchloride 2b (209 mg, 0.75 mmol), N-phenylben-
zylidene amine 1 (91 mg, 0.5 mmol) and silylketene acetal 3 (131 mg,
0.75 mmol) in CH2Cl2 (4 mL) after chromatography with hexane/acetone
3:1 as a colorless oil (54%) in a 93:7 mixture of diastereomers. TLC: Rf ˆ
0.20 (hexane/acetone 8:1); HPLC: tR ˆ 13'32'' (methanol/H2O 80:20);
1H NMR (400 MHz, CDCl3): d ˆ 7.62 (m, 4H), 7.51 (d, J ˆ 8 Hz, 1H), 7.40
(dd, J ˆ 8, 8 Hz, 1H), 7.14 ± 7.19 (m, 5H), 7.09 (d, J ˆ 7 Hz, 1H), 6.36 (s, 1H),
6.31 (dd, J ˆ 8, 8 Hz, 1H), 5.43 (d, J ˆ 8 Hz, 1H), 4.48 (s, 1H), 3.63 (s, 3H),
1.34 (s, 3H), 1.22 (s, 3H), 1.12 (s, 9H); 13C NMR (100.6 MHz, CDCl3): d ˆ
176.86 (q), 167.08 (q), 166.73 (q), 139.01 (q), 137.45 (q), 133.72 (CH), 131.47
(CH), 131.43 (CH), 131.26 (CH), 130.31 (CH), 129.22 (CH), 128.02 (CH),
127.69 (CH), 127.60 (CH), 127.48 (CH), 122.94 (CH), 65.35 (CH), 58.02
(CH), 51.96 (CH3), 47.58 (q), 37.15 (q), 27.70 (CH3), 24.74 (CH3), 24.28
(CH3); MS(70 eV, EI): m/z (%): 526 (3), 425 (46), 282 (8), 244 (33), 216
(100); C32H34N2O5 (526.63): calcd C 72.98, H 6.51, N 5.32; found: C 72.80, H
‡
for [M] : 225.1154, found: 225.1143.
N-(2-Methoxy-6-methylphenyl)-4'-chlorobenzylidene amine (6j): The
product was obtained as an orange oil after removing the unreacted
starting materials by Kugelrohr distillation. Although the 1H NMR still
showed some traces of the unreacted amine, the product was used for the
next reaction without further purification (73%). 1H NMR (400 MHz,
CDCl3): d ˆ 8.42 (s, 1H), 7.89 (d, J ˆ 9 Hz, 2H), 7.47 (d, J ˆ 9 Hz, 2H), 7.04
(dd, J ˆ 8, 8 Hz, 1H), 6.88 (d, J ˆ 8 Hz, 1H), 6.86 (d, J ˆ 8 Hz, 1H), 3.78 (s,
3H), 2.26 (s, 3H); 13C NMR (100.4 MHz, CDCl3): d ˆ 162.44 (CH), 149.52
(q), 140.04 (q), 137.19 (q), 135.07 (q), 131.43 (q), 129.73 (CH), 128.94 (CH),
124.69 (CH), 122.72 (CH), 109.55 (CH), 55.86 (CH3),18.15 (CH3); MS
(70 eV, EI): m/z (%): 259 (36), 244 (9), 209 (3), 137 (94), 122 (100); HR-MS
‡
(70 eV, EI): m/z: calcd for [M] : 259.0764, found: 259.0747.
N-(2-Methoxy-4-methylphenyl)-2'-methoxybenzylidene amine (6k): The
product was obtained as a yellow solid after recrystallization from ethanol
(85% aqueous). Yield 83%; m.p.: 868C; 1H NMR (500 MHz, CDCl3): d ˆ
8.79 (s, 1H), 8.25 (dd, J ˆ 2, 7 Hz, 1H), 7.41 (ddd, J ˆ 2, 7, 7 Hz, 1H), 7.04
(dd, J ˆ 7, 7 Hz, 1H), 6.96 (dd, J ˆ 8, 8 Hz, 1H), 6.91 (d, J ˆ 8 Hz, 1H), 6.82
(d, J ˆ 8 Hz, 1H), 6.79 (d, J ˆ 8 Hz, 1H), 3.83 (s, 3H), 3.73 (s, 3H), 2.20 (s,
3H); 13C NMR (125.8 MHz, CDCl3): d ˆ 160.01 (CH), 159.39 (q), 149.65
(q), 141.57 (q), 132.46 (CH), 130.64 (q), 127.25 (CH), 124.93 (q), 124.03
(CH), 122.57 (CH), 120.76 (CH), 111.08 (CH), 109.46 (CH), 55.87 (CH3),
55.49 (CH3), 18.10 (CH3); MS(70 eV, EI): m/z (%): 255 (79), 240 (4), 225
(18), 148 (5), 137 (100), 122 (49); C16H17NO2 (255.32): calcd C 75.27, H 6.71,
N 5.49; found: C 75.17, H 6.68, N 5.45; HR-MS(70 eV, EI): m/z: calcd for
‡
6.80, N 5.28; HR-MS(70 eV, EI): m/z: calcd for [M] : 526.2468, found:
526.2485.
Methyl
2,2-dimethyl-(R)-3-phenyl-3-[N-phenyl-N-((S)-N',N'-phthaloyl-
tert-leucyl)]-amino-propionate (5b): Characteristic analytic data for the
minor product. HPLC: tR ˆ 14'49'' (methanol/H2O 80:20); 1H NMR
(400 MHz, CDCl3): d ˆ 4.30 (s, 1H), 3.65 (s, 3H), 1.07 (s, 9H).
Methyl 3-[N-(S)-benzyloxycarbonyl-prolyl-N-phenyl]-amino-2,2-dimeth-
yl-(S)-3-phenyl-propionate (4c) and methyl 3-[N-(S)-benzyloxycarbonyl-
prolyl-N-phenyl]-amino-2,2-dimethyl-(R)-3-phenyl-propionate (5c): The
products were obtained from N-benzyloxycarbonyl-prolylchloride (2c,
348 mg, 1.3 mmol) after chromatography with hexane/acetone 12:1 as a
‡
[M] : 255.1259; found: 255.1247.
1
colorless oil (69%) in a 53:47 mixture of diastereomers. The H- and 13C-
N-(2-Methoxy-4-methylphenyl)-4'-methoxybenzylidene amine (6l): The
product was obtained as a red oil after removing the unreacted starting
materials by Kugelrohr distillation (53%). 1H NMR (500 MHz, CDCl3):
d ˆ 8.30 (s, 1H), 7.86 (d, J ˆ 9 Hz, 2H), 6.97 (d, J ˆ 9 Hz, 2H), 6.97 (dd, J ˆ
8, 8 Hz, 1H), 6.83 (d, J ˆ 8 Hz, 1H), 6.79 (d, J ˆ 8 Hz, 1H), 3.85 (s, 3H), 3.73
(s, 3H), 2.21 (s, 3H); 13C NMR (125.8 MHz, CDCl3): d ˆ 163.06 (CH),
162.12 (q), 149.69 (q), 140.97 (q), 130.98 (q), 130.19 (CH), 129.50 (q), 124.04
(CH), 122.60 (CH), 114.00 (CH), 109.48 (CH), 55.82 (CH3), 55.35 (CH3),
18.08 (CH3); MS(70 eV, EI): m/z (%): 255 (52), 240 (10), 136 (70), 135
(100), 122 (60); C16H17NO2 (255.32): calcd C 75.27, H 6.71, N 5.49; found: C
NMR spectra showed not only the two diastereomers but also rotamers.
The assignment of the signal groups was made by analysis of the 1H/1H- and
1H/13C-COSY spectra. TLC: Rf ˆ 0.16 (hexane/acetone 8:1); HPLC: tR ˆ
23'51'' major product 4c and 22'16'' minor product 5c (methanol/H2O
75:25); 1H NMR (500 MHz, CDCl3): d ˆ {7.44, 7.61 (d, 3J ˆ 8 Hz; o-phenyl-
H)}, 6.96 ± 7.39 (m; arom. CH), 6.98 (d, 3J ˆ 7 Hz; o-phenyl-H), 6.77 (d, 3J ˆ
7 Hz; o-phenyl-H), 6.70 (ddd, 4J ˆ 1 Hz, 3J1 ˆ 3J2 ˆ 8 Hz; m-phenyl-H),
{5.85, 6.50, 6.54 (d, 3J ˆ 8 Hz; o-phenyl-H)}, {5.72, 6.06, 6.13 (s, 1H;
PhCHN)}, {5.07, 5.15 (d, 2J ˆ 5 Hz, 1H; CH2-benzyl)}, {4.76, 4.94, 5.04, 5.32
(d, 2J ˆ 12 Hz, 1H, CH2-benzyl)}, {3.79, 3.98, 4.01, 4.15 (ddd, 3J1 ˆ 4 Hz,
3J2 ˆ 8 Hz, 1H; aH)}, 3.62 ± 3.70 (m, 1H; 5H-proline), {3.54, 3.57, 3.65 (s,
3H; OCH3)}, 3.42 ± 3.51 (m, 1H; 5H-proline), 1.95 ± 2.05 (m, 1H; 4H-
proline), 1.81 ± 1.87 (m, 1H; 3H-proline), 1.70 ± 1.76 (m, 1H; 3H-proline),
1.62 ± 1.69 (m, 1H; 4H-proline), {1.17, 1.20, 1.25, 1.30, 1.31, 1.35, 1.38 (s, 6H;
(CH3)2C)}; 13C NMR (125.8 MHz, CDCl3): d ˆ {176.67, 176.89, 176.93,
177.03 (q; CO2CH3)}, {173.54, 173.71 (q; C(O)-proline)}, {154.00, 154.08,
154.52, 154.59 (q; C(O)-Z)}, {128.64, 128.88, 130.49, 130.71, 131.03, 131.24,
131.41, 131.82, 132.45 (CH; arom. CH)}, {127.56, 136.10, 136.41, 136.68,
136.85, 136.95, 137.60, 137.67, 139.76, 140.62, 140.71, 140.90 (q; arom. C)},
{127.54, 127.66, 127.70, 127.75, 127.80, 127.89, 127.93, 128.18, 128.22, 128.33,
128.38, 128.47, 128.81, 129.12, 130.25, 130.63, 130.98, 132.38 (CH; arom.
CH)}, {67.36, 68.98 (CH; PhCHN)}, {57.58, 57.63, 58.12, 58.28 (CH; aC)},
{65.64, 66.68, 66.90, 67.09, 67.20 (CH2; CH2Ph)}, {51.76, 51.88, 51.96 (CH3;
OCH3)}, {47.51, 47.62, 47.79, 47.83 (q; (CH3)2C)}, {46.95, 47.01, 47.46, 47.55
(CH2; 5C-proline)}, {30.38, 31.00,31.42 (CH2; 3C-proline)}, {23.24, 23.30,
24.22, 29.93 (CH2; 4C-proline)}, {22.94, 23.56, 24.29, 24.77, 24.86, 24.93,
25.06, 25.13, 25.36 (CH3; (CH3)2C)}; MS(70 eV, EI): m/z (%): 514 (3), 413
(22), 232 (9), 204 (22), 91 (100); HR-MS(70 eV, EI): m/z: calcd for
(C31H34N2O5): 514.2468, found: 514.2485.
‡
75.48, H 6.79, N 5.45; HR-MS(70 eV, EI): m/z: calcd for [M] : 255.1259,
found: 255.1248.
Amidoalkylation of 1-methoxy-2-methyl-1-trimethylsiloxypropene (3)
with N-phenylbenzylideneamine (1) and the amino acid chlorides 2a ± d.
General procedure: Acid chloride 2 (1.5 mmol) in dry CH2Cl2 (3 mL) was
added under argon at 08C to a solution of the Schiff base 1 (181 mg,
1 mmol) in dry CH2Cl2 (3 mL). The mixture was kept at 08C for 10 min and
then warmed to room temperature over 30 min. After cooling the solution
to 08C, silylketene acetal 3 (261 mg, 1.5 mmol) was added over 5 min. The
solution was kept at room temperature for an additional 72 h. After
addition of CH2Cl2 (10 mL), the mixture was washed with 10% aq.
NaHCO3 (10 mL) and brine (10 mL), and dried over Na2SO4. After
evaporation to dryness, the residue was purified by chromatography on
silica gel.
Methyl 2,2-dimethyl-(S)-3-phenyl-3-[N-phenyl-N-((S)-N',N'-phthaloylval-
yl)]-amino-propionate (4a): The products were obtained from N,N-
phthaloyl valine chloride (2a, 265 mg, 1 mmol) after chromatography with
hexane/acetone 9:1 as a colorless oil (80%) in a 87:13 mixture of
diastereomers. TLC: Rf ˆ 0.14 (hexane/acetone 9:1); HPLC: tR ˆ 82'28''
2038
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
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Chem. Eur. J. 2000, 6, No. 11

Mannich Reaction
2032±2043
Mannich reaction of N,N-phthaloyl-tert-leucylchloride (2b), the Schiff
bases 6a ± l and 1-methoxy-2-methyl-1-trimethylsiloxy propene (3). Gen-
eral procedure: Acid chloride 2b (336 mg, 1.2 mmol) in dry CH2Cl2 (3 mL)
was added under argon at 08C to a solution of N-aryl-arylidene amine 6
(1 mmol) in dry CH2Cl2 (3 mL). The mixture was kept at 08C for 10 min
and then warmed to room temperature over 30 min. After cooling the
solution to 08C silylketene acetal 3 (261 mg, 1.5 mmol) was added over
5 min. The solution was kept at room temperature for an additional 72 h.
After addition of CH2Cl2 (10 mL), the mixture was washed with 10% aq.
NaHCO3 (10 mL) and brine (10 mL), and dried over Na2SO4. After
evaporation to dryness, the residue was purified by chromatography on
silica gel.
(CH3); MS(70 eV, EI): m/z (%): 569 (3), 468 (68), 225 (25), 234 (17), 216
(100); C34H39N3O5 (569.70): calcd C 71.68, H 6.90, N 7.38; found: C 71.63, H
‡
6.91, N 7.28; HR-MS(70 eV, EI): m/z: calcd for [M] : 569.2890, found:
569.2878.
Methyl 2,2-dimethyl-(R)-3-[4'-(N,N-dimethylaminophenyl]-3-[N-phenyl-
N-((S)-N',N'-phthaloyl-tert-leucyl)]-amino-propionate (9d): Characteristic
analytic data for the minor product. HPLC: tR ˆ 21'6'' (methanol/H2O
75:25); 1H NMR (400 MHz, CDCl3): d ˆ 7.71 (s, 4H), 4.26 (s, 1H), 3.63 (s,
3H), 2.92 (s, 6H), 1.08 (s, 9H).
Methyl 2,2-dimethyl-(S)-3-(4'-methoxyphenyl)-3-[N-phenyl-N-((S)-N',N'-
phthaloyl-tert-leucyl)]-amino-propionate (8e): The products were ob-
tained from acid chloride 2b (169 mg, 0.6 mmol), N-(4-methoxyphenyl)-
benzylidene amine (6e, 105 mg, 0.5 mmol) and silylketene acetal 3 (131 mg,
0.75 mmol) in CH2Cl2 (4 mL) after chromatography with hexane/ethyl
acetate 3:1 as a colorless oil (84%) in a 92:8 mixture of diastereomers.
TLC: Rf ˆ 0.18 (hexane/acetone 6:1); HPLC: tR ˆ 17'24'' (methanol/H2O
75:25); 1H NMR (400 MHz, CDCl3): d ˆ 7.53 ± 7.62 (m, 4H), 7.51 (d, J ˆ
9 Hz, 1H), 7.39 (ddd, J ˆ 1, 8, 8 Hz, 1H), 7.08 (dd, J ˆ 8, 8 Hz, 1H), 7.02 (d,
J ˆ 9 Hz, 2H), 6.65 (dd, J ˆ 9, 9 Hz, 2H), 6.32 (ddd, J ˆ 1, 8, 8 Hz, 1H), 6.31
(s, 1H), 5.43 (d, J ˆ 9 Hz, 1H), 4.44 (s, 1H), 3.73 (s, 3H), 3,62 (s, 3H), 1.30
(s, 3H), 1.19 (s, 3H), 1.09 (s, 9H); 13C NMR (100.6 MHz, CDCl3): d ˆ
176.94 (q), 166.94 (q), 166.75 (q), 158.84 (q), 138.87 (q), 133.73 (CH), 132.51
(CH), 131.46 (CH), 130.59 (CH), 129.41 (q), 129.20 (CH), 127.99 (CH),
127.43 (CH), 122.99 (CH), 112.85 (CH), 64.59 (CH), 57.97 (CH), 55.04
(CH3), 51.98 (CH3), 47.76 (q), 37.15 (q), 27.69 (CH3), 24.71 (CH3), 24.16
(CH3); MS(70 eV, EI): m/z (%): 556 (4), 455 (19), 336 (6), 244 (15), 216
(100); C33H36N2O6 (556.66): calcd C 71.20, H 6.52, N 5.03; found: C 71.15, H
Methyl (S)-3-(4-chlorophenyl)-3-[N-phenyl-N-((S)-N',N'-phthaloyl-tert-
leucyl)]-amino-2,2-dimethyl-propionate (8b): The products were obtained
from acid chloride 2b (168 mg, 0.6 mmol), N-(4-chlorophenyl)-benzylidene
amine (6b, 108 mg, 0.5 mmol) and silylketene acetal 3 (131 mg, 0.75 mmol)
in CH2Cl2 (4 mL) after chromatography with hexane/ethyl acetate 3:1 as a
colorless oil (44%) in a 92:8 mixture of diastereomers. TLC: Rf ˆ 0.25
(hexane/acetone 6:1); HPLC: tR ˆ 13'55'' (methanol/H2O 80:20); 1H NMR
(500 MHz, CDCl3): d ˆ 7.63 (m, 4H), 7.44 (ddd, J ˆ 2, 8, 8 Hz, 1H), 7.40
(ddd, J ˆ 2, 8, 8 Hz, 1H), 7.12 (m, 5H), 6.38 (ddd, J ˆ 2, 8, 8 Hz, 1H), 6.31 (s,
1H), 5.51 (d, J ˆ 8 Hz, 1H), 4.45 (s, 1H), 3.61 (s, 3H), 1.30 (s, 3H), 1.21 (s,
3H), 1.10 (s, 9H); 13C NMR (125.8 MHz, CDCl3): d ˆ 176.63 (q), 167.18 (q),
166.80 (q), 138.86 (q), 136.09 (q), 133.88 (CH), 133.66 (q), 132.63 (CH),
131.43 (q), 131.35 (CH), 130.12 (CH), 129.49 (CH), 128.28 (CH), 127.88
(CH), 127.78 (CH), 123.08 (CH), 64.73 (CH), 58.00 (CH), 52.09 (CH3), 47.50
(q), 37.23 (q), 27.70 (CH3), 24.61 (CH3), 24.49 (CH3); MS(70 eV, EI): m/z
(%): 560 (3), 459 (8), 316 (6), 244 (25), 216 (100); C32H33ClN2O5 (561.07):
calcd C 68.50, H 5.93, N 4.99; found: C 68.64, H 6.17, N 4.67; HR-MS(70 eV,
‡
6.61, N 4.84; HR-MS(70 eV, EI): m/z: calcd for [M] : 556.2573, found:
556.2593.
‡
EI): m/z: calcd for [M] : 560.2078, found: 560.2095.
Methyl 2,2-dimethyl-(R)-3-(4-methoxyphenyl)-3-[N-phenyl-N-((S)-N',N'-
phthaloyl-tert-leucyl)]-amino-propionate (9e): Characteristic analytic data
for the minor product. HPLC: tR ˆ 18'34'' (methanol/H2O 75:25); 1H NMR
(400 MHz, CDCl3): d ˆ 7.69 (m, 4H), 5.68 (s, 1H), 4.26 (s, 1H), 3.77 (s, 3H),
3,63 (s, 3H), 1.04 (s, 9H).
Methyl (R)-3-(4-chlorophenyl)-3-[N-phenyl-N-((S)-N',N'-phthaloyl-tert-
leucyl)]-amino-2,2-dimethyl-propionate (9b): Characteristic analytic data
for the minor product. HPLC: tR ˆ 14'41'' (methanol/H2O 80:20); 1H NMR
(500 MHz, CDCl3): d ˆ 7.69 (m, 4H), 4.30 (s, 1H), 3.65 (s, 3H), 1.06 (s, 9H).
Methyl
2,2-dimethyl-(S)-3-(2,4,6-trimethylphenyl)-3-[N-phenyl-N-((S)-
Methyl 2,2-dimethyl-(S)-3-phenyl-3-[N-(4'-methoxy-phenyl-N-((S)-N',N'-
phthaloyl-tert-leucyl)]-amino-propionate (8g): The products were ob-
tained from acid chloride 2b (230 mg, 0.82 mmol), N-(4-methoxyphenyl)-
benzylidene amine (6g, 158 mg, 0.75 mmol) and silylketene acetal 3
(195 mg, 1.12 mmol) in CH2Cl2 (4 mL) after chromatography with hexane/
acetone 10:1 as a colorless oil (82%) in a 91:9 mixture of diastereomers. To
determine the optical rotation, an analytical sample was obtained after
separation by HPLC. The major product 8g was obtained as a pure
diastereomer. TLC: Rf ˆ 0.23 (hexane/acetone 3:1); HPLC: tR ˆ 17'43''
(methanol/H2O 75:25); [a]2D2 ˆ À64.0 (c ˆ 0.5, CHCl3); 1H NMR
(400 MHz, CDCl3): d ˆ 7.61 (s, 4H), 7.43 (dd, J ˆ 3, 9 Hz, 1H), 7.16 ± 7.19
(m, 5H), 6.88 (dd, J ˆ 3, 9 Hz, 1H), 6.35 (s, 1H), 5.78 (dd, J ˆ 3, 9 Hz, 1H),
5.27 (dd, J ˆ 3, 9 Hz, 1H), 4.45 (s, 1H), 3.68 (s, 3H), 3.64 (s, 3H), 1.33 (s,
3H), 1.20 (s, 3H), 1.10 (s, 9H); 13C NMR (100.6 MHz, CDCl3): d ˆ 176.94
(q), 167.36 (q), 166.75 (q), 158.91 (q), 137.32 (q), 133.68 (CH), 132.43 (CH),
131.59 (CH), 131.48 (q), 131.36 (CH), 127.66 (CH), 127.59 (CH), 122.91
(CH), 113.90 (CH), 113.02 (CH), 64.87 (CH), 57.95 (CH), 55.31 (CH3),
52.02 (CH3), 47.57 (q), 37.14 (q), 27.70 (CH3), 24.79 (CH3), 24.06 (CH3); MS
(70 eV, EI): m/z (%): 556 (5), 455 (40), 312 (4), 244 (26), 216 (100);
C33H36N2O6 (556.66): calcd C 71.20, H 6.52, N 5.03; found: C 71.06, H 6.69,
N',N'-phthaloyl-tert-leucyl)]-amino-propionate (8c): The product was
obtained from acid chloride 2b (210 mg, 0.75 mmol), N-phenyl-2,4,6-
trimethylbenzylidene amine (6c, 112 mg, 0.5 mg) and silylketene acetal 3
(131 mg, 0.75 mmol) in CH2Cl2 (3 mL) after chromatography with hexane/
acetone 15:1 as a colorless solid (46%). M.p.: 2378C; TLC: Rf ˆ 0.30
(hexane/acetone 6:1); HPLC: tR ˆ 24'45'' (methanol/H2O 80:20); [a]D22
ˆ
À86.8 (c ˆ 0.5 in CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 7.63 (s, 4H), 7.20
(ddd, J ˆ 2, 8, 8 Hz, 1H), 7.04 (dd, J ˆ 8, 8 Hz, 1H), 6.99 (dd, J ˆ 8, 8 Hz,
1H), 6.69 (s, 1H), 6.40 (ddd, J ˆ 2, 8, 8 Hz, 1H), 6.59 (s, 1H), 6.19 (d, J ˆ
8 Hz, 1H), 6.20 (s, 1H), 4.43 (s, 1H), 3.84 (s, 3H), 2.16 (s, 3H), 2.12 (s, 3H),
1.77 (s, 3H), 1.54 (s, 3H), 1.12 (s, 3H), 1.09 (s, 9H); 13C NMR (125.8 MHz,
CDCl3): d ˆ 178.08 (q), 166.70 (q), 165.73 (q), 140.81 (q), 139.91 (q), 139.15
(q), 136.71 (q), 133.63 (CH), 131.02 (q), 130.36 (q), 130.34 (CH), 130.31
(CH), 129.93 (CH), 129.27 (CH), 129.14 (CH), 128.10 (CH), 127.54 (CH),
123.01 (CH), 66.68 (CH), 58.57 (CH), 52.17 (CH3), 48.53 (q), 37.32 (q), 27.85
(CH3), 23.71 (CH3), 22.11 (CH3), 21.89 (CH3), 20.67 (CH3); MS(70 eV, EI):
m/z (%): 568 (1), 537 (1), 467 (45), 324 (3), 244 (27), 216 (100); C35H40N2O5
(568.71): calcd C 73.92, H 7.09, N 4.93; found: C 73.99, H 7.18, N 4.83; HR-
‡
MS(70 eV, EI): m/z: calcd for [M] : 568.2937, found: 568.2960.
‡
Methyl 2,2-dimethyl-(S)-3-[4'-(N,N-dimethylaminophenyl)]-3-[N-phenyl-
N-((S)-N',N'-phthaloyl-tert-leucyl)]-amino-propionate (8d): The products
were obtained from of N-phenyl-4-dimethylaminobenzylidene amine (6d,
224 mg, 1 mmol) after chromatography with hexane/ethyl acetate 3:1 as a
yellow oil (91%) as a 91:9 mixture of diastereomers. To determine the
optical rotation, an analytical sample was obtained after separation by
HPLC. The major product 8d was obtained as a pure diastereomer. TLC:
Rf ˆ 0.18 (hexane/acetone 6:1); HPLC: tR ˆ 19'2'' (methanol/H2O 75:25);
[a]2D2 ˆ À206.1 (c ˆ 0.5 in CHCl3); 1H NMR (400 MHz, CDCl3): d ˆ 7.61 (s,
4H), 7.56 (d, J ˆ 8 Hz, 1H), 7.40 (ddd, J ˆ 1, 8, 8 Hz, 1H), 7.08 (dd, J ˆ 7,
7 Hz, 1H), 6.90 (d, J ˆ 9 Hz, 2H), 6.46 (d, J ˆ 9 Hz, 2H), 6.35 (ddd, J ˆ 1, 7,
8 Hz, 1H), 6.24 (s, 1H), 5.50 (d, J ˆ 8 Hz, 1H), 4.46 (s, 1H), 3.64 (s, 3H),
2.88 (s, 6H), 1.30 (s, 3H), 1.19 (s, 3H), 1.10 (s, 9H); 13C NMR (100.6 MHz,
CDCl3): d ˆ 177.12 (q), 166.77 (q), 149.63 (q), 139.02 (q), 133.64 (CH),
132.21 (CH), 131.55 (CH), 130.99 (CH), 129.02 (CH), 127.81 (CH), 127.29
(CH), 124.66 (q), 122.97 (CH), 111.25 (CH), 64.87 (CH), 57.98 (CH), 51.91
(CH3), 47.95 (q), 40.27 (CH3), 37.14 (q), 27.73 (CH3), 24.87 (CH3), 23.92
N 5.01; HR-MS(70 eV, EI): m/z: calcd for [M] : 556.2573, found: 556.2556.
Methyl 2,2-dimethyl-(R)-3-phenyl-3-[N-(4-methoxyphenyl)-N-((S)-N',N'-
phthaloyl-tert-leucyl)]-amino-propionate (9g): Characteristic analytic data
for the minor product. HPLC: tR ˆ 19'57'' (methanol/H2O 75:25); 1H NMR
(400 MHz, CDCl3): d ˆ 7.61 (s, 4H), 7.41 (dd, J ˆ 3, 9 Hz, 1H), 4.27 (s, 1H),
3.71 (s, 3H), 3.65 (s, 3H), 1.05 (s, 9H).
Methyl 2,2-dimethyl-(S)-3-phenyl-3-[N-(2'-methoxy-6'-methylphenyl)-N-
((S)-N',N'-phthaloyl-tert-leucyl)]-amino-propionate (8h): The product
was obtained from acid chloride 2b (838 mg, 3 mmol), N-(2-methoxy-6-
methylphenyl)-benzylidene amine (6h, 451 mg, 2 mmol) and silylketene
acetal 3 (523 mg, 3 mmol) in CH2Cl2 (12 mL) after chromatography with
hexane/acetone 10:1 as a colorless solid (50%). M.p.: 1978C; TLC: Rf ˆ
0.22 (hexane/acetone 6:1); HPLC: tR ˆ 17'52'' (methanol/H2O 80:20);
[a]2D2 ˆ À79.9 (c ˆ 0.5 in CHCl3); 1H NMR (400 MHz, CDCl3): d ˆ 7.73 (d,
J ˆ 7 Hz, 1H), 7.61 (dd, J ˆ 7, 7 Hz, 2H), 7.49 (d, J ˆ 7 Hz, 1H), 7.06 (dd, J ˆ
8, 8 Hz, 2H), 6.96 (dd, J ˆ 8, 8 Hz, 2H), 6.85 (s, 2H), 6.83 (s, 1H), 6.37 (s,
Chem. Eur. J. 2000, 6, No. 11
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0611-2039 $ 17.50+.50/0
2039

H. Waldmann et al.
FULL PAPER
1H), 6.05 (d, J ˆ 8 Hz, 1H), 4.33 (s, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 1.54 (s,
3H), 1.16 (s, 3H), 1.09 (s, 9H), 0.65 (s, 3H); 13C NMR (100.6 MHz, CDCl3)
d ˆ 177.25 (q), 167.68 (q), 166.32 (q), 155.91 (q), 140.92 (q), 136.12 (q),
133.59 (CH), 132.32 (q), 131.95 (CH), 130.74 (q), 129.19 (CH), 127.47 (CH),
127.35 (q), 127.01 (CH), 123.02 (CH), 122.78 (CH), 122.41 (CH), 109.59
(CH), 66.76 (CH), 58.50 (CH), 54.74 (CH3), 51.78 (CH3), 49.91 (q), 37.40
(q), 27.93 (CH3), 24.39 (CH3), 22.33 (CH3), 17.55 (CH3); MS(70 eV, EI): m/z
(%): 570 (0.4), 539 (1), 469 (38), 326 (4), 244 (11), 226 (37), 216 (100);
C34H38N2O6 (570.68): calcd C 71.56, H 6.71, N 4.91; found: C 71.56, H 6.75,
128.06 (q), 125.25 (q), 122.87 (CH), 122.67 (CH), 122.27 (CH), 118.66 (CH),
110.11 (CH), 109.29 (CH), 58.60 (CH), 58.45 (CH), 55.87 (CH3), 54.57
(CH3), 51.63 (CH3), 48.75 (q), 37.26 (q), 27.92 (CH3), 24.05 (CH3), 28.85
(CH3), 17.26 (CH3); MS(70 eV, EI): m/z (%): 600 (1), 569 (3), 499 (100), 356
(4), 256 (64), 216 (81); C35H40N2O7 (600.71 ): calcd C 69.98, H 6.71, N 4.66;
‡
found: C 70.11, H 6.68, N 4.67; HR-MS(70 eV, EI): m/z: calcd for [M] :
600.2836, found: 600.2856.
Methyl 2,2-dimethyl-(S)-3-(4'-methoxyphenyl)-3-[N-(2'-methoxy-6'-meth-
ylphenyl)-N-((S)-N',N'-phthaloyl-tert-leucyl)]-amino-propionate (8l): The
product was obtained from N-(2-methoxy-6-methylphenyl)-4'-methoxy-
benzylidene amine (6l, 257 mg, 1 mmol) after chromatography with
hexane/ethyl acetate 3:1 as a colorless solid (75%). TLC: Rf ˆ 0.09
(hexane/ethyl acetate 3:1); HPLC: tR ˆ 24'32'' (methanol/H2O75:25);
[a]2D2 ˆ À98.5 (c ˆ 0.5 in CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 7.74
(d, J ˆ 7 Hz, 1H), 7.65 (ddd, J ˆ 1, 7, 7 Hz, 1H), 7.61 (ddd, J ˆ 1, 7, 7 Hz,
1H), 7.51 (d, J ˆ 7 Hz, 1H), 7.08 (dd, J ˆ 8, 8 Hz, 1H), 6.86 (d, J ˆ 8 Hz,
1H), 6.71 ± 6.75 (br, 2H), 6.50 (d, J ˆ 8 Hz, 2H), 6.44 (s, 1H), 6.08 (d, J ˆ
8 Hz, 1H), 4.34 (s, 1H), 3.95 (s, 3H), 3.67 (s, 3H), 3.60 (s, 3H), 1.54 (s, 3H),
1.16 (s, 3H), 1.11 (s, 9H), 0.65 (s, 3H); 13C NMR (125.8 MHz, CDCl3): d ˆ
177.21 (q), 167.47 (q), 166.27 (q), 158.74 (q), 155.87 (q), 141.07 (q), 133.85
(CH), 133.53 (CH), 132.29 (q), 130.68 (q), 129.12 (CH), 128.29 (q), 127.11
(q), 122.95 (CH), 122.71 (CH), 122.36 (CH), 112.27 (CH), 109.50 (CH),
65.52 (CH), 58.41 (CH), 54.92 (CH3), 54.69 (CH3), 51.69 (CH3), 50.14 (q),
37.32 (q), 27.86 (CH3), 24.40 (CH3), 21.34 (CH3), 17.57 (CH3); MS(70 eV,
EI): m/z (%): 600 (2), 569 (2), 499 (63), 380 (16), 256 (33), 221 (28), 216
(100); C35H40N2O7 (600.71 ): calcd C 69.98, H 6.71, N 4.66; found: C 69.86,
‡
N 4.82; HR-MS(70 eV, EI): m/z: calcd for [M] : 570.2730, found: 570.2753.
Methyl 2,2-dimethyl-(S)-3-(2'-methoxyphenyl)-3-[N-phenyl-N-((S)-N',N'-
phthaloyl-tert-leucyl)]-amino-propionate (8i): The products were obtained
after chromatography with hexane/acetone 12:1 as a colorless oil (91%) in
a 92:8 mixture of diastereomers. To determine the optical rotation, an
analytical sample was obtained after separation by HPLC. The major
product 8i was obtained as a pure diastereomer. TLC: Rf ˆ 0.16 (hexane/
acetone 6:1); HPLC: tR ˆ 19'43'' (methanol/H2O 77:23); [a]2D2 ˆ À122.0
(c ˆ 0.5 in CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 7.63 (br, 4H), 7.45 (d,
J ˆ 8 Hz, 1H), 7.35 (ddd, J ˆ 1, 8, 8 Hz, 1H), 7.14 (ddd, J ˆ 1, 8, 8 Hz, 1H),
7.06 (dd, J ˆ 8, 8 Hz, 1H), 6.81 (ddd, J ˆ 1, 8, 8 Hz, 1H), 6.79 (d, J ˆ 8 Hz,
1H), 6.58 (dd, J ˆ 8, 8 Hz, 1H), 6.57 (s, 1H), 6.35 (ddd, J ˆ 1, 8, 8 Hz, 1H),
5.68 (d, J ˆ 8 Hz, 1H), 4.42 (s, 1H), 3.77 (s, 3H), 3.67 (s, 3H), 1.35 (s, 3H),
1.29 (s, 3H), 1.10 (s, 9H); 13C NMR (125.6 MHz, CDCl3): d ˆ 177.27 (q),
166.75 (q), 166.58 (q), 158.20 (q), 139.82 (q), 133.68 (CH), 132.03 (CH),
131.62 (q), 131.19 (CH), 130.81 (CH), 129.05 (CH), 128.84 (CH), 127.76
(CH), 127.46 (CH), 125.87 (CH), 122.95 (CH), 119.14 (CH), 110.86 (CH),
58.35 (CH), 56.02 (CH3), 51.88 (CH3), 47.87 (q), 37.24 (q), 27.81 (CH3), 25.13
(CH3), 24.56 (CH3); MS(70 eV, EI): m/z (%): 556 (1), 525 (2), 455 (46), 312
(5), 244 (20), 216 (100); C33H36N2O6 (556.66): calcd C 71.20, H 6.52, N 5.03;
‡
H 6.72, N 4.83; HR-MS(70 eV, EI): m/z: calcd for [M] : 600.2836, found:
600.2823.
Mannich reaction of N,N-phthaloyl-tert-leucylchloride (2b), the Schiff
bases 6h,l,k and 1-ethoxy-1-trimethylsiloxy-ethene (7). General procedure:
Acid chloride 2b (168 mg, 0.6 mmol) was added in dry CH2Cl2 (3 mL) to a
solution of of the Schiff base (0.5 mmol) in dry CH2Cl2 (2 mL) under argon
at 08C. The mixture was stirred for 10 min and then allowed to warm to
room temperature over 30 min. After cooling the solution to 08C,
silylketene acetal 7 (120 mg, 0.75 mmol) was added over 5 min. The
solution was then stirred at room temperature for 72 h. After addition of
CH2Cl2 (10 mL), the mixture was washed with 10% aq. NaHCO3 (10 mL)
and brine (10 mL) and dried over Na2SO4. After evaporation to dryness,
the residue was purified by chromatography on silica gel with hexane/ethyl
acetate 3:1.
‡
found: C 71.17, H 6.49, N 4.89; HR-MS(70 eV, EI): m/z: calcd for [M] :
556.2573, found: 556.2590.
Methyl 2,2-dimethyl-(R)-3-(2'-methoxyphenyl)-3-[N-phenyl-N-((S)-N',N'-
phthaloyl-tert-leucyl)]-amino-propionate (9i): Characteristic analytic data
1
for the minor product. HPLC: tR ˆ 17'3'' (methanol/H2O 77:23); H NMR
(500 MHz, CDCl3): d ˆ 7.69 (br, 4H), 6.20 (s, 1H), 4.33 (s, 1H), 3.72 (s, 3H),
3.54 (s, 3H), 1.09 (s, 9H).
Methyl
(S)-3-(4'-chlorophenyl)-3-[N-(2'-methoxy-6'-methylphenyl)-N-
(8j):
((S)-N',N'-phthaloyl-tert-leucyl)]-amino-2,2-dimethyl-propionate
The product was obtained from N-(2-methoxy-6-methylphenyl)-4'-chlor-
obenzylidene amine (6j, 260 mg, 1 mmol) after chromatography with
hexane/ethyl acetate 3:1 as a colorless solid (26%). TLC: Rf ˆ 0.22
(hexane/ethyl acetate 3:1); HPLC: tR ˆ 14'46'' (methanol/H2O 82:18);
Ethyl (R)-3-[N-(2'-methoxy-6'-methylphenyl)-N-((S)-N',N'-phthaloyl-tert-
leucyl)]-amino-3-phenyl-propionate 8m. The product was obtained from
N-(2-methoxy-6-methylpheny)-benzylidene amine (6h, 113 mg, 0.5 mmol)
as a 96:4 mixture of diastereomers (34%). To determine the optical
rotation, an analytical sample was obtained after separation by HPLC. The
major product 8m was obtained as a pure diastereomer (colorless oil).
TLC: Rf ˆ 0.19 (hexane/ethyl acetate 3:1); HPLC: tR ˆ 16''55' (minor)
18'21'' (major) (methanol/water 75:25); [a]2D2 ˆ À90.0 (c ˆ 0.5 in CHCl3);
1H NMR (400 MHz, CDCl3): d ˆ 7.80 (d, J ˆ 7 Hz, 1H), 7.66 (dd, J ˆ 7, 7 Hz,
1H), 7.64 (dd, J ˆ 7, 7 Hz, 1H), 7.55 (d, J ˆ 7 Hz, 1H), 7.06 ± 7.12 (m, 6H),
6.79 (d, J ˆ 8 Hz, 1H), 6.26 (d, J ˆ 8 Hz, 1H), 5.62 (dd, J ˆ 5, 9 Hz, 1H),
4.17 (s, 1H), 3.92 (q, J ˆ 7 Hz, 2H), 3.68 (s, 3H), 3.30 (dd, J ˆ 16, 5 Hz, 1H),
3.28 (dd, J ˆ 16, 9 Hz, 1H), 1.08 (s, 9H), 1.03 (t, J ˆ 7 Hz, 3H), 0.91 (s, 3H);
13C NMR (100.6 MHz, CDCl3): d ˆ 171.24 (q); 168.33 (q), 167.74 (q), 166.53
(q), 155.45 (q), 138.99 (q), 137.91 (q), 133.99 (CH), 133.72 (CH), 132.23 (q),
130.87 (q), 129.90 (CH), 128.99 (CH), 127.58 (CH), 127.53 (CH), 127.29 (q),
123.09 (CH), 122.91 (CH), 122.78 (CH), 109.43 (CH), 60.29 (CH), 60.18
(CH2), 58.14 (CH), 55.11 (CH3), 32.00 (CH2), 37.02 (q), 27.69 (CH3), 17.01
(CH3), 13.97 (CH3), MS(70 eV, EI): m/z (%): 556 (6), 452 (1), 396 (2), 312
(2), 216 (100); HR-MS(70 eV, EI): m/z: calcd for (C33H36N2O6): 556.2573,
found: 556.2608.
1
[a]2D2 ˆ À87.9 (c ˆ 0.5 in CHCl3); H NMR (500 MHz, CDCl3): d ˆ 7.77 (d,
J ˆ 7 Hz, 1H), 7.67 (ddd, J ˆ 1, 7, 7 Hz, 1H), 7.63 (ddd, J ˆ 1, 7, 7 Hz, 1H),
7.52 (d, J ˆ 7 Hz, 1H), 7.09 (dd, J ˆ 8, 8 Hz, 1H), 6.98 (d, J ˆ 8 Hz, 2H), 6.88
(d, J ˆ 8 Hz, 2H), 6.84 (d, J ˆ 8 Hz, 1H), 6.19 (s, 1H), 6.15 (d, J ˆ 8 Hz,
1H), 4.34 (s, 1H), 3.87 (s, 3H), 3.61 (s, 3H), 1.52 (s, 3H), 1.23 (s, 3H), 1.11 (s,
9H), 0.81 (s, 3H); 13C NMR (125.8 MHz, CDCl3): d ˆ 176.87 (q), 167.87 (q),
167.44 (q), 166.18 (q), 155.69 (q), 140.13 (q), 134.89 (q), 133.94 (CH), 133.63
(CH), 133.41 (q), 133.18 (CH), 132.17 (q), 130.62 (q), 129.29 (CH), 127.27
(q), 127.04 (CH), 122.95 (CH), 122.76 (CH), 122.54 (CH), 109.69 (CH),
66.65 (CH3), 58.36 (CH3), 54.64 (CH), 51.75 (CH), 49.63 (q), 37.28 (q), 27.83
(CH3), 24.67 (CH3), 22.32 (CH3), 17.70 (CH3); MS(70 eV, EI): m/z (%): 604
(1), 573 (2), 545 (1), 503 (43), 360 (6), 244 (25), 216 (100); C34H37N2O6
(604.13): calcd C 67.49, H 6.16, N, 4.63; found: C 67.22, H 6.29, N 4.85; HR-
‡
MS(70 eV, EI): m/z: calcd for [M] : 604.2340, found: 604.2356.
Methyl 2,2-dimethyl-(S)-3-(2'-methoxyphenyl)-3-[N-(2'-methoxy-6'-meth-
ylphenyl)-N-((S)-N',N'-phthaloyl-tert-leucyl)]-amino-propionate
(8k):
The product was obtained from N-(2-methoxy-6-methylphenyl)-2'-me-
thoxybenzylidene amine (6k, 255 mg, 1 mmol) after chromatography with
hexane/ethyl acetate 3:1 as a colorless solid (59%). TLC: Rf ˆ 0.16
(hexane/ethyl acetate 3:1); HPLC: tR ˆ 19'40'' (methanol/H2O 77:23);
[a]2D2 ˆ À103.4 (c ˆ 0.5 in CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 7.77 (d,
J ˆ 7 Hz, 1H), 7.65 (ddd, J ˆ 1, 7, 7 Hz, 1H), 7.61 (ddd, J ˆ 1, 7, 7 Hz, 1H),
7.50 (d, J ˆ 7 Hz, 1H), 7.03 (ddd, J ˆ 1, 8, 8 Hz, 1H), 6.99 (dd, J ˆ 8, 8 Hz,
1H), 6.84 (d, J ˆ 8 Hz, 1H), 6.73 (d, J ˆ 8 Hz, 1H), 6.63 (d, J ˆ8 Hz, 1H),
6.59 (s, 1H), 6.52 (dd, J ˆ 8, 8 Hz, 1H), 6.07 (d, J ˆ 8 Hz, 1H), 4.34 (s, 1H),
3.81 (s, 3H), 3.66 (s, 3H), 3.65 (s, 3H), 1.47 (s, 3H), 1.21 (s, 3H), 1.11 (s, 9H),
0.96 (s, 3H); 13C NMR (125.8 MHz, CDCl3): d ˆ 177.33 (q), 167.75 (q),
167.34 (q), 166.30 (q), 157.95 (q), 155.69 (q), 140.05 (CH), 133.77 (CH),
133.46 (CH), 132.71 (CH), 132.30 (q), 130.85 (q), 128.61 (CH), 128.28 (CH),
Ethyl
(S)-3-(4'-methoxyphenyl)-3-[N-(2'-methoxy-6'-methylphenyl)-N-
((S)-N',N'-phthaloyl-tert-leucyl)]-amino-propionate (8n): The product
was obtained from N-(2-methoxy-6-methylphenyl)-4'-methoxybenzylidene
amine (6l, 128 mg, 0.5 mmol). Colorless solid (68%); m.p.: 1928C; TLC:
Rf ˆ 0.11 (hexane/acetone 6:1); HPLC: tR ˆ 20'25'' (methanol/H2O 70:30);
[a]2D2 ˆ À102.6 (c ˆ 0.5 in CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 7.81 (d,
J ˆ 7 Hz, 1H), 7.68 (dd, J ˆ 7, 7 Hz, 1H), 7.64 (dd, J ˆ 7, 7 Hz, 1H), 7.56 (d,
J ˆ 7 Hz, 1H), 7.09 (dd, J ˆ 8, 8 Hz, 1H), 6.96 (dd, J ˆ 7, 2 Hz, 2H), 6.81 (d,
J ˆ 8 Hz, 1H), 6.60 (dd, J ˆ 7, 2 Hz, 2H), 6.26 (d, J ˆ 8 Hz, 1H), 5.66 (dd,
J ˆ 11, 4 Hz, 1H), 4.18 (s, 1H), 3.95 (dq, J ˆ 30, 7 Hz, 1H), 3.93 (dq, J ˆ 30,
2040
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0611-2040 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 11

Mannich Reaction
2032±2043
7 Hz, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 3.31 (dd, J ˆ 16, 4 Hz, 1H), 3.19 (dd,
J ˆ 16 Hz, 11 Hz, 1H), 1.09 (s, 9H), 1.06 (ddd, J ˆ 12, 7, 7 Hz, 3H), 0.91 (s,
3H); 13C NMR (125.8 MHz, CDCl3): d ˆ 171.27 (q), 168.21 (q), 167.74 (q),
166.56 (q), 158.97 (q), 155.52 (q), 139.23 (q), 133.98 (CH), 133.70 (CH),
132.30 (q), 131.09 (CH), 130.92 (q), 130.09 (q), 128.98 (CH), 127.12 (q),
123.11 (CH), 122.93 (CH), 122.81 (CH), 112.85 (CH), 109.40 (CH), 60.18
(CH2), 59.52 (CH), 58.18 (CH), 55.18 (CH3), 55.08 (CH3), 38.23 (CH2),
37.06 (q), 27.73 (CH3), 17.15 (CH3), 14.04 (CH3); MS(70 eV, EI): m/z (%):
586 (86), 541 (14), 380 (74), 324 (35), 216 (80), 207 (100); C34H38N2O7
(586.68): calcd C 69.61, H 6.53, N 4.77; found: C 69.64, H 6.49, N 4.85; HR-
(400 MHz, CDCl3): d ˆ 8.11 (d, J ˆ 8 Hz, 1H), 7.62 (br, 4H), 7.47 (ddd, J ˆ
8, 8, 1 Hz, 1H), 7.13 (dd, J ˆ 8, 8 Hz, 1H), 6.92 (s, 1H), 6.81 (d, J ˆ 12 Hz,
1H), 6.40 (s, 1H), 6.35 (ddd, J ˆ 8, 8, 1 Hz, 1H), 5.42 (d, J ˆ 8 Hz, 1H), 4.50
(ddd, J ˆ 10, 9, 7 Hz, 1H), 4.59 (s, 1H), 4.32 (ddd, J ˆ 10, 9, 3 Hz, 1H), 3.30
(ddd, J ˆ 12, 9, 3 Hz, 1H), 2.59 (s, 3H), 2.30 (ddd, J ˆ 9, 10, 13 Hz, 1H), 2.17
(s, 3H), 1.70 (ddd, J ˆ 3, 7, 13 Hz, 1H), 1.12 (s, 12H); 13C NMR (100.6 MHz,
CDCl3): d ˆ 177.27 (q), 166.30 (q), 140.82 (q), 138.26 (q), 137.57 (q), 137.50
(q), 133.69 (CH), 130.94 (CH), 130.42 (CH), 130.25 (CH), 130.18 (CH),
130.08 (CH), 129.60 (q), 128.30 (CH), 128.13 (CH), 123.00 (CH), 66.34
(CH2), 57.49 (CH), 54.50 (CH), 39.34 (CH), 37.25 (q), 27.80 (CH3), 27.37
(CH2), 21.68 (CH3), 20.67 (CH3); MS(70 eV, EI): m/z (%): 552 (22), 496 (6),
336 (20), 308 (30), 280 (15), 216 (100); HR-MS(70 eV, EI): m/z: calcd for
‡
MS(70 eV, EI): m/z: calcd for [M] : 586.2679, found: 586.2700.
Ethyl
(R)-3-(2'-methoxyphenyl)-3-[N-(2'-methoxy-6'-methylphenyl)-N-
‡
[M] : 552.2624, found: 552.2626.
((S)-N',N'-phthaloyl-tert-leucyl)]-amino-propionate (8o): The product
was obtained from N-(2-methoxy-6-methylphenyl)-2'-methoxybenzylidene
amine (6k, 128 mg, 0.5 mmol). Colorless solid (51%); m.p.: 1728C; TLC:
Rf ˆ 0.12 (hexane/ethyl acetate 3:1); HPLC: tR ˆ 20'0'' (methanol/H2O
70:30); [a]2D2 ˆ À136.1 (c ˆ 0.5 in CHCl3); 1H NMR (400 MHz, CDCl3): d ˆ
7.81 (d, J ˆ 7 Hz, 1H), 7.68 (ddd, J ˆ 1, 7, 7 Hz, 1H), 7.64 (ddd, J ˆ 1, 7, 7 Hz,
1H), 7.57 (d, J ˆ 7 Hz, 1H), 7.06 (dd, J ˆ 8, 8 Hz, 1H), 7.06 (dd, J ˆ 8, 8 Hz,
1H), 6.98 (d, J ˆ 8, 8 Hz, 1H), 6.79 (d, J ˆ 8 Hz, 1H), 6.64 (d, J ˆ 8 Hz, 1H),
6.62 (dd, J ˆ 8, 8 Hz, 1H), 6.32 (dd, J ˆ 4, 11 Hz, 1H), 6.23 (d, J ˆ 8 Hz,
1H), 4.18 (s, 1H), 3.93 (dq, J ˆ 31, 7 Hz, 1H), 3.90 (dq, J ˆ 31, 7 Hz, 1H),
3.75 (s, 3H), 3.55 (s, 3H), 3.35 (dd, J ˆ 16, 4 Hz, 1H), 3.25 (dd, J ˆ 16, 11 Hz,
1H), 1.09 (s, 9H), 1.01 (dd, J ˆ 7, 7 Hz, 3H), 0.87 (s, 3H):13C NMR
(100.6 MHz, CDCl3): d ˆ 171.39 (q), 168.30 (q), 167.47 (q), 166.60 (q),
158.28 (q), 155.67 (q), 139.34 (q), 133.91 (CH), 133.62 (CH), 132.33 (q),
131.00 (q), 130.25 (CH), 128.65 (CH), 128.58 (CH), 127.44 (q), 125.97 (q),
122.94 (CH), 122.88 (CH), 122.51 (CH), 119.56 (CH), 109.75 (CH), 108.87
(CH), 59.94 (CH2), 58.03 (CH), 55.19 (CH3), 55.06 (CH3), 52.05 (CH), 37.10
(q), 37.01 (CH2), 27.75 (CH3),16.56 (CH3), 13.93 (CH3); MS(70 eV, EI): m/z
(%): 586 (99), 541 (16), 380 (80), 324 (41), 216 (100), 207 (19); C34H38N2O7
(586.68): calcd C 69.61, H 6.53, N 4.77; found: C 69.39, H 6.61, N 4.67; HR-
Methyl
(S)-3-[N-phenyl-N-((S)-N',N'-phthaloyl-tert-leucyl)]-amino-3-
(2,4,6-trimethylphenyl)-(R)-2-methoxy-propionate (14syn): The product
was obtained from the same reaction mixture as 14anti after additional
chromatography with hexane/dichloromethane 1:6. Colorless solid (70%);
m.p.: 2358C; TLC: Rf ˆ 0.29 (hexane/ethyl acetate 3:1); HPLC: tR ˆ 18'58''
(methanol/H2O 75:25); [a]D22 ˆ À98 (c ˆ 0.5, CHCl3); H NMR (500 MHz,
1
CDCl3): d ˆ 7.86 (d, J ˆ 8 Hz, 1H), 7.61 (br, 4H), 7.45 (ddd, J ˆ 2, 8, 8 Hz,
1H), 7.12 (dd, J ˆ 8, 8 Hz, 1H), 6.85 (s, 1H), 6.67 (d, J ˆ 11 Hz, 1H), 6.37 (s,
1H), 6.32 (ddd, J ˆ 2, 8, 8 Hz, 1H), 5.37 (d, J ˆ 8 Hz, 1H), 4.46 (s, 1H), 4.36
(d, J ˆ 11 Hz, 1H), 3.93 (s, 3H), 3.24 (s, 3H), 2.51 (s, 3H), 2.15 (s, 3H), 1.13
(s, 3H), 1.09 (s, 9H); 13C NMR (125.8 MHz, CDCl3): d ˆ 172.58 (q), 166.13
(q), 140.51 (q), 139.14 (q), 137.77 (q), 137.06 (q), 133.71 (CH), 130.49 (CH),
130.46 (CH), 130.19 (CH), 129.88 (CH), 129.86 (CH), 129.28 (q), 128.30
(CH), 128.00 (CH), 123.06 (q), 79.52 (CH), 57.83 (CH3), 57.58 (CH), 56.62
(CH), 52.54 (CH3), 37.23 (q), 27.90 (CH3), 21.43 (CH3), 20.75 (CH3), 19.84
(CH3); MS(70 eV, EI): m/z (%): 570 (0.1), 539 (0.4), 511 (1), 467 (48), 244
(23), 216 (100); C34H38N2O6 (570.682): calcd C 71.56, H 6.71, N 4.91; found:
‡
C 71.18, H 6.67, N 4.73; HR-MS(70 eV, EI): m/z: calcd for [M] : 570.2730,
found: 570.2755.
‡
MS(70 eV, EI): m/z: calcd for [M] : 586.2679, found: 586.2664.
Methyl
(S)-3-[N-phenyl-N-((S)-N',N'-phthaloyl-tert-leucyl)]-amino-3-
(2,4,6-trimethylphenyl)-(S)-2-methoxy-propionate (14anti): The product
was obtained from (Z)-1,2-dimethoxy-1-trimethyl siloxy-ethene 11
(132 mg, 0.75 mmol) after chromatography with hexane/ethyl acetate 4:1.
Colorless oil (7%); TLC: Rf ˆ 0.23 (hexane/ethyl acetate 3:1); HPLC: tR ˆ
18'2'' (methanol/H2O 75:25); [a]2D2 ˆ À21 (c ˆ 0.5 in CHCl3); 1H NMR
(500 MHz, CDCl3): d ˆ 7.62 (s, 4H), 7.45 (ddd, J ˆ 1, 8, 8 Hz, 1H), 7.29 (d,
J ˆ 8 Hz, 1H), 7.16 (dd, J ˆ 8, 8 Hz, 1H), 6.84 (d, J ˆ 10 Hz, 1H), 6.81 (s,
1H), 6.46 (ddd, J ˆ 1, 8, 8 Hz, 1H), 6.38 (s, 1H), 5.64 (d, J ˆ 8 Hz, 1H), 4.47
(d, J ˆ 10 Hz, 1H), 4.46 (s, 1H), 3.54 (s, 3H), 3.52 (s, 3H), 2.51 (s, 3H), 2.13
(s, 3H), 1.23 (s, 3H), 1.12 (s, 9H); 13C NMR (125.8 MHz, CDCl3): d ˆ
170.66 (q), 166.84 (q), 165.61 (q), 140.70 (q), 138.64 (q), 138.35 (q), 137.24
(q), 133.67 (CH), 131.52 (q), 130.63 (CH), 130.49 (CH), 130.07 (CH), 129.86
(CH), 129.62 (CH), 129.12 (q), 128.60 (CH), 128.35 (CH), 123.07 (CH),
80.99 (CH), 57.99 (CH), 57.85 (CH3), 51.86 (CH3), 37.11 (q), 27.60 (CH3),
21.79 (CH3), 20.77 (CH3); MS(70 eV, EI): m/z (%): 570 (0.1), 539 (0.5), 511
Mannich reaction with N,N-phthaloyl-tert-leucylchloride (2b), N-phenyl-
2,4,6-trimethylbenzylidene amine (6c), and the silylketene acetals 10, 11
and 12. General procedure: Acid chloride 2b (168 mg, 0.6 mmol) in dry
CH2Cl2 (3 mL) was added under argon at 08C to a solution of of Schiff base
6c (112 mg, 0.5 mmol) in dry CH2Cl2 (2 mL). The mixture was kept at 08C
for 10 min and then warmed to room temperature over 1 h. After cooling
the solution to 08C the silylketene acetal (0.75 mmol) was added over
5 min. The solution was then stirred at room temperature for 72 h. After
addition of CH2Cl2 (10 mL), the mixture was washed with 10% aq.
NaHCO3 (10 mL) and brine (10 mL) and dried over Na2SO4. After
evaporation to dryness, the residue was purified by chromatography on
silica gel.
(R)-2-{(R)-[N-Phenyl-N-((S)-N',N'-phthaloyl-tert-leucyl)]-amino-(2',4',6'-
trimethylphenyl)-methyl}-butano-4-lactone (13syn): The product was ob-
tained from Schiff base 6c (223 mg, 1 mmol), acid chloride 2b (308 mg,
1.1 mmol) and 2-trimethylsiloxydihydrofuran (10, 237 mg, 0.75 mmol) after
chromatography with hexane/acetone 12:1). Colorless solid (47%);
m.p.: 1868C; TLC: Rf ˆ 0.06 (hexane/acetone 6:1); HPLC: tR ˆ 15'22''
(methanol/H2O 72:28); [a]2D2 ˆ À82.9 (c ˆ 0.5 in CHCl3); 1H NMR
(400 MHz, CDCl3): d ˆ 7.63 (br, 4H), 7.42 (ddd, J ˆ 8, 8, 1 Hz, 1H), 7.23
(d, J ˆ 8 Hz, 1H), 7.15 (dd, J ˆ 8, 8 Hz, 1H), 6.81 (s, 1H), 6.65 (d, J ˆ 10 Hz,
1H), 6.39 (ddd, J ˆ 8, 8, 1 Hz, 1H), 6.38 (s, 1H), 4.45 (d, J ˆ 8 Hz, 1H), 4.58
(ddd, J ˆ 16, 8, 6 Hz, 1H), 4.46 (s, 1H), 4.30 (ddd, J ˆ 16, 8, 6 Hz, 1H), 3.46
(ddd, J ˆ 10, 16, 8 Hz, 1H), 2.60 ± 2.70 (m, 1H), 2.53 ± 2.59 (m, 1H), 2.50 (s,
3H), 2.12 (s, 3H), 1.27 (s, 3H), 1.11 (s, 9H); 13C NMR (100.6 MHz, CDCl3):
d ˆ 175.85 (q), 166.49 (q), 139.52 (q), 138.94 (q), 137.30 (q), 137.21 (q),
133.93 (CH), 130.67 (CH), 130.45 (CH), 130.13 (q), 129.77 (CH), 129.35
(CH), 128.62 (CH), 128.55 (CH), 123.16 (CH), 66.09 (CH2), 57.80 (CH),
55.66 (CH), 41.95 (CH), 37.13 (q), 27.78 (CH2), 27.67 (CH3), 21.62 (CH3),
21.28 (CH3), 20.76 (CH3); MS(70 eV, EI): m/z (%): 552 (18), 496 (6), 336
(20), 308 (27), 280 (14), 216 (100); C34H36N2O3 (552.67): calcd C 73.89, H
6.57, N 5.07; found: C 73.60, H 6.40, N 4.93; HR-MS(70 eV, EI): m/z: calcd
‡
(1), 467 (48), 244 (21), 216 (100); HR-MS(70 eV, EI): m/z: calcd for [M] :
570.2730, found: 570.2748.
Methyl
(S)-3-[N-phenyl-N-((S)-N',N'-phthaloyl-tert-leucyl)]-amino-3-
(2,4,6-trimethylphenyl)-(R)-2-(tert-butyl-dimethyl)-siloxy-propionate
(15syn): The product was obtained from (E)-1-(dimethyl-tert butylsiloxy)-
2-methoxy, 2-trimethylsiloxy-ethene 12 (207 mg, 0.75 mmol) after chroma-
tography with hexane/ethyl acetate 10:1. Colorless solid (66%);
m.p.: 1978C; TLC: Rf ˆ 0.17 (hexane/ethyl acetate 10:1); HPLC: tR
ˆ
11'13'' (methanol/H2O 75:25); [a]2D2 ˆ À91.8 (c ˆ 0.5 in CHCl3); 1H NMR
(500 MHz, CDCl3): d ˆ 7.62 (s, 4H), 7.34 (d, J ˆ 8 Hz, 1H), 7.29 (ddd, J ˆ 1,
8, 8 Hz, 1H), 7.07 (dd, J ˆ 7, 7 Hz, 1H), 6.67 (s, 1H), 6.49 (s, 1H), 6.44 (ddd,
J ˆ 1, 8, 8 Hz, 1H), 6.08 (d, J ˆ 10 Hz, 1H), 6.00 (d, J ˆ 8 Hz, 1H), 5.12 (d,
J ˆ 10 Hz, 1H), 4.37 (s, 1H), 3.88 (s, 3H), 2.16 (s, 3H), 2.13 (s, 3H), 1.64 (s,
3H), 1.07 (s, 9H), 0.55 (s, 9H), À0.06 (s, 3H), À0.31 (s, 3H); 13C NMR
(125.8 MHz, CDCl3): d ˆ 172.54 (q), 166.72 (q), 165.87 (q), 140.41 (q),
139.52 (q), 138.15 (q), 136.74 (q), 133.68 (CH), 131.54 (q), 130.23 (CH),
130.19 (CH), 130.06 (q), 129.82 (CH), 129.61 (CH), 129.09 (CH), 128.29
(CH), 128.01 (CH), 123.05 (q), 72.31 (CH), 61.67 (CH), 57.94 (CH), 51.90
(CH3), 37.14 (q), 27.86 (CH3), 25.31 (CH3), 21.25 (CH3), 20.69 (CH3), 20.36
(CH3), 17.87 (q), À4.79 (CH3), À5.19 (CH3); MS(70 eV, EI): m/z (%): 670
(0.3), 613 (16), 585 (5), 467 (78), 244 (28), 216 (100); C39H50N2O6Si (670.92):
calcd C 69.82, H 7.51, N 4.18; found: C 69.83, H 7.42, N 4.05; HR-MS(70 eV,
‡
for [M] : 552.2624, found: 552.2607.
(S)-2-{(R)-[N-Phenyl-N-((S)-N',N'-phthaloyl-tert-leucyl)]-amino-(2',4',6'-
trimethylphenyl)-methyl}-butano-4-lactone (13anti): colorless solid
(28%); m.p.: 1748C; TLC: Rf ˆ 0.11 (hexane/acetone 6:1); HPLC: tR ˆ
20'44'' (methanol/H2O 72:28); [a]2D2 ˆ À77.4 (c ˆ 0.5 in CHCl3); 1H NMR
‡
EI): m/z: calcd for [M] : 670.3438, found: 670.3422.
Chem. Eur. J. 2000, 6, No. 11
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0611-2041 $ 17.50+.50/0
2041

H. Waldmann et al.
FULL PAPER
Modified procedure for the cleavage of the N,N-phthaloyl group. General
procedure: NaBH4 (4 mg, 0.1 mmol) was added to a solution of of methyl-
(S)-3-aryl-3-[N-aryl-N-((S)-N',N'-phthaloyl-tert-leucyl)]-amino-2,2-di-
methyl-propionate (0.09 mmol) in isopropanol/water 7:1 (1.6 mL). The
reaction mixture was stirred at room temperature until a TLC showed the
consumption of the starting material. By addition of concentrated HCl
(aqueous, 0.36 mmol, 30 mL) the pH of the solution was adjusted to pH 1.
After stirring at 808C until a TLC showed the consumption of the
intermediate product, the solution was neutralised with aq. NaHCO3 and
extracted with CH2Cl2 (5 mL). The combined organic layers were dried
over Na2SO4 and the solvent removed in vacuo. The residue was added
onto a plug of silica gel, washed with hexane/acetate 3:1 and eluted with
pure ethyl acetate.
Modified procedure for carrying out the Edman degradation. General
procedure: Phenylisothiocyanate (25 mg, 0.183 mmol) was added to a
solution of one of the above mentioned amines (0.091 mmol) in water/
pyridine 1:1 (5 mL). To this solution was slowly added 1 equivalent of
aqueous NaOH (0.2m, 0.9 mL) at room temperature. After stirring for 3 h,
the reaction mixture was extracted with toluene and the organic solvent
removed in vacuum. The residue was dissolved in a mixture of CH2Cl2
(5 mL) and TFA (1 mL) and refluxed until a TLC: of the reaction mixture
showed the disappearance of the starting material. After neutralisation
with aq. NaHCO3 and extraction with CH2Cl2 (10 mL) the combined
organic layers were dried over Na2SO4. After filtration the solution was
evaporated to dryness and the amine was obtained by column chromatog-
raphy on silica gel.
Methyl 2,2-dimethyl-(S)-3-phenyl-amino-3-(2',4',6'-trimethylphenyl)-pro-
pionate (20a): The product was obtained after hydrolysis of methyl 2,2-
dimethyl-(S)-3-[N-(tert-leucyl)-N-phenyl]-amino-3-(2',4',6'-trimethylphen-
yl)-propionate (18a, 66 mg, 0.151 mmol) in a mixture of CH2Cl2 (8 mL) and
TFA (2.3 mL). Column chromatography with hexane/actone 40:1 afforded
the product as a yellow oil (59%). TLC: Rf ˆ 0.51 (hexane/acetone 4:1);
[a]2D2 ˆ À69.4 (c ˆ 1.13 in CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 7.04
(ddd, J ˆ 2, 7, 7 Hz, 2H), 6.85 (s, 1H), 6.68 (s, 1H), 6.58 (ddd, J ˆ 1, 7, 7 Hz,
1H), 6.40 (dd, J ˆ 1, 9 Hz, 2H), 5.03 (s, 1H), 4.61 (br, 1H), 3.68 (s, 3H), 2.56
(s, 3H), 2.29 (s, 3H), 2.21 (s, 3H), 1.33 (s, 3H), 1.23 (s, 3H); 13C NMR
(125.8 MHz, CDCl3): d ˆ 177.58 (q), 147.16 (q), 137.90 (q), 137.05 (q), 136.19
(q), 132.04 (CH), 131.23 (q), 129.89 (CH), 129.10 (CH), 116.80 (CH), 112.37
(CH), 60.61 (CH3), 52.33 (CH), 48.55 (q), 25.61 (CH3), 22.33 (CH3), 22.08
(CH3), 21.46 (CH3), 20.62 (CH3); IR (KBr, drift): nÄ ˆ 3408, 2955, 1719, 1518,
1499, 1432, 1389, 1367, 1273, 1254, 1074, 852, 751, 723 cmÀ1, MS(70 eV, EI):
m/z (%): 325 (3), 224 (100), 104 (7); C21H27NO2 (325.45): calcd C 77.50, H
8.36, N 4.30; found: C 77.37, H 8.18, N 4.25; HR-MS(70 eV, EI): m/z: calcd
Methyl 2,2-dimethyl-(S)-3-(2',4',6'-trimethylphenyl)-3-[N-phenyl-N-((S)-
tert-leucyl)]-amino-propionate (18a): The product was obtained from of
methyl 2,2-dimethyl-(S)-3-(2',4',6'-trimethylphenyl)-3-[N-phenyl-N-((S)-
N',N'-phthaloyl-tert-leucyl)]-amino-propionate (8c, 60 mg, 0.11 mmol) in
isopropanol/water 7:1 (12 mL) as a colorless oil (88%); TLC: Rf ˆ 0.08
(hexane/ethyl acetate 4:1); [a]2D2 ˆ À38 (c ˆ 1.31 in CHCl3); 1H NMR
(500 MHz, CDCl3): d ˆ 7.46 (d, J ˆ 8 Hz, 1H), 7.34 (ddd, J ˆ 1, 7, 7 Hz, 1H),
7.23 (dd, J ˆ 7, 7 Hz, 1H), 7.08 (ddd, J ˆ 1, 8, 8 Hz, 1H), 6.63 (s, 1H), 6.81 (s,
1H), 6.57 (d, J ˆ 8 Hz, 1H), 5.63 (s, 1H), 3.75 (s, 3H), 2.74 (s, 1H), 2.28 (s,
3H), 2.12 (s, 3H), 1.80 (s, 3H), 1.56 (s, 3H), 1.50 (br, 2H), 1.16 (s, 3H), 0.87
(s, 9H); 13C NMR (125.8 MHz, CDCl3): d ˆ 177.62 (q), 175.35 (q), 144.09
(q), 139.16 (q), 139.08 (q), 136.72 (q), 130.79 (CH), 130.41 (q), 130.30 (CH),
129.69 (CH), 129.02 (CH), 128.93 (CH), 128.30 (CH), 127.80 (CH), 69.19
(CH), 59.89 (CH), 51.87 (CH3), 49.23 (q), 34.28 (q), 29.20 (CH3), 27.72
(CH3), 23.62 (CH3), 22.17 (CH3), 21.66 (CH3), 20.68 (CH3); MS(70 eV, EI):
m/z (%): 438 (0.2), 407 (1), 338 (7), 264 (7), 147 (6), 86 (100); HR-MS
(70 eV, EI): m/z: calcd for (C27H38N2O3): 438.2882, found: 438.2898.
‡
for [M] : 325.2042, found: 325.2032.
Methyl
2,2-dimethyl-(S)-3-[N-(4'-methoxyphenyl)-N-((S)-tert-leucyl)]-
Methyl
2,2-dimethyl-3-(4'-methoxyphenyl)-amino-3-phenyl-propionate
amino-3-phenyl-propionate (18b) and methyl 2,2-dimethyl-(R)-3-[N-(4'-
methoxyphenyl)-N-((S)-tert-leucyl)]-amino-3-phenyl-propionate (18b):
The product was obtained from of a 92:8 mixture (11 mg, 0.02 mmol) of
the diastereomers methyl 2,2-dimethyl-(S)-3-[N-(4'-methoxyphenyl)-N-
((S)-N',N'-phthaloyl-tert-leucyl)]-amino-3-phenyl-propionate (8g) and
methyl 2,2-dimethyl-(R)-3-[N-(4'-methoxyphenyl)-N-((S)-N',N'-phthaloyl-
tert-leucyl)]-amino-3-phenyl-propionate (9g) as a colorless oil (97%) as a
92:8 mixture of the diastereomers 18b and 19b. TLC: Rf ˆ 0.17 (hexane/
(20b): The product was obtained from methyl 2,2-dimethyl-3-[N-(tert-
leucyl)-N-(4'-methoxyphenyl)]-amino-3-phenyl-propionate (18b, 39 mg,
0.091 mmol) as a pale yellow oil after column chromatography with
hexane/acetone 30:1 and gave correct analytical data according to the
literature.[30] Yield 84%; TLC: Rf ˆ 0.36 (hexane/acetone 3:1); 1H NMR
(250 MHz, CDCl3): d ˆ 7.27 (s, 5H), 6.62 (d, J ˆ 9 Hz, 2H), 6.43 (d, J ˆ
9 Hz, 2H), 4.44 (s, 1H), 3.66 (s, 3H), 2.18 (s, 1H), 1.25 (s, 3H),1.16 (s, 3H);
IR (KBr, drift): nÄ ˆ 3368, 3070, 3028, 2834, 1733, 1715, 1617, 1514, 1391,
1035, 824, 806, 764 cmÀ1; MS(70 eV, EI): m/z (%): 313 (8), 212 (100), 196
(3), 168 (3); HR-MS(70 eV, EI): m/z: calcd for (C19H23NO3):313.1678,
found: 313.1689.
1
acetone 2:1); H NMR (400 MHz, CDCl3): d ˆ 7.28 (dd, J ˆ 3, 9 Hz, 1H),
7.11 (m, 2H), 6.88 (dd, J ˆ 3, 9 Hz, 1H), 6.63 (dd, J ˆ 3, 9 Hz, 1H), 6.38 (dd,
J ˆ 3, 9 Hz, 1H), 3.79 (s, 3H), 6.15 (s, 1H), 3.64 (s, 3H), 2.74 (s, 1H), 1.27 (s,
3H), 1.21 (s, 3H), 0.88 (s, 9H); 13C NMR (100.6 MHz, CDCl3): d ˆ 177.02
(q), 176.74 (q), 159.08 (q), 136.84 (q), 133.53 (q), 132.48 (CH), 132.31 (CH),
131.41 (CH), 127.73 (CH), 127.59 (CH), 113.32 (CH), 66.06 (CH), 58.99
(CH), 55.35 (CH3), 51.99 (CH3), 47.45 (q), 34.73 (q), 26.45 (CH3), 26.14
(CH3), 23.27 (CH3); MS(70 eV, EI): m/z (%): 426 (1), 395 (2), 369 (2), 341
(23), 212 (36), 86 (100); C25H34N2O4 (426.55): calcd C 70.40, H 8.03, N 6.57;
Methyl 2,2-dimethyl-(S)-3-(2'-methoxy-6'-methylphenyl)-amino-3-phenyl-
propionate (20c): The product was obtained after hydrolysis of methyl 2,2-
dimethyl-(S)-3-[N-(tert-leucyl)-N-(2'-methoxy-6'-methylphenyl)]-amino-3-
phenyl-propionate (18c, 66 mg, 0.150 mmol) in a mixture of CH2Cl2
(7.8 mL) and TFA (1.6 mL). Column chromatography with hexane/ethyl
acetate 25:1 gave the product as a colorless oil (45%). TLC: Rf ˆ 0.13
‡
found: C 70.32, H 7.86, N 6.53; HR-MS(70 eV, EI): m/z: calcd for [M] :
1
(hexane/ethyl acetate 25:1); [a]2D2 ˆ À46.3 (c ˆ 1.045 in CHCl3); H NMR
426.2519, found: 426.2527. Characteristic data of the minor diastereomer
19b: 1H NMR (400 MHz, CDCl3): d ˆ 3.78 (s, 3H), 3.61 (s, 3H), 2.89 (s,
1H), 0.77 (s, 9H).
(500 MHz, CDCl3): d ˆ 7.11 ± 7.19 (m, 5H), 6.61 (dd, J ˆ 7, 7 Hz, 1H), 6.56
(dd, J ˆ 2, 7 Hz, 2H), 5.02 (s, 1H), 4.84 (s, 1H), 3.81 (s, 3H), 3.65 (s, 3H),
2.25 (s, 3H), 1.22 (s, 3H), 1.20 (s, 3H); 13C NMR (125.8 MHz, CDCl3): d ˆ
177.27 (q), 149.93 (q), 139.76 (q), 135.40 (q), 128.34 (CH), 127.55 (q), 127.44
(CH), 126.99 (CH), 123.89 (CH), 119.84 (CH), 108.35 (CH), 66.28 (CH),
55.71 (q), 51.78 (CH3), 47.42 (CH3), 24.68 (CH3), 19.95 (CH3), 19.48 (CH3);
IR (KBr, drift): nÄ ˆ 3387, 3067, 3027, 2950, 2838, 1734, 1608, 1587, 1506, 1467,
1429, 1388, 1377, 764, 704 cmÀ1, MS(70 eV, EI): m/z (%): 237 (6), 226 (100),
210 (5); C20H25NO3 (327.42): calcd C 73.37, H 7.70, N 4.28, found: C 73.36, H
Methyl 2,2-dimethyl-(S)-3-[N-(2'-methoxy-6'-methylphenyl)-N-((S)-tert-
leucyl)]-amino-3-phenyl-propionate (18c): The product was obtained from
of methyl 2,2-dimethyl-(S)-3-[N-(2'-methoxy-6'-methylphenyl)-N-((S)-
N',N'-phthaloyl-tert-leucyl)]-amino-3-phenyl-propionate (8h, 174 mg,
0.31 mmol) in isopropanol/water 7:1 (25 mL) after column chromatography
with hexane/ethyl acetate 3:1 as a colorless oil (65%). TLC: Rf ˆ 0.11
(hexane/ethyl acetate 3:1); [a]2D2 ˆ ‡78 (c ˆ 0.55, CHCl3); 1H NMR
(500 MHz, CDCl3): d ˆ 7.17 (dd, J ˆ 8, 8 Hz, 1H), 7.15 (dd, J ˆ 7, 7 Hz,
1H), 7.05 (dd, J ˆ 7, 7 Hz, 2H), 6.99 (d, J ˆ 7 Hz, 2H), 6.75 (d, J ˆ 8 Hz,
1H), 6.56 (d, J ˆ 8 Hz, 1H), 6.54 (s, 1H), 3.82 (s, 3H), 3.64 (s, 3H), 2.63 (s,
1H), 1.47 (s, 3H), 1.38 (s, 3H), 1.07 (s, 3H), 0.93 (s, 9H); 13C NMR
(125.8 MHz, CDCl3): d ˆ 177.58 (q), 177.48 (q), 156.30 (q), 140.92 (q),
135.94 (q), 131.74 (CH), 129.18 (CH), 128.77 (q), 127.54 (CH), 127.21 (CH),
122.92 (CH), 108.33 (CH), 65.84 (CH), 60.10 (CH), 54.15 (CH3), 51.86
(CH3), 48.78 (q), 34.67 (q), 26.55 (CH3), 24.56 (CH3), 22.80 (CH3), 18.35
(CH3); MS(70 eV, EI): m/z (%): 440 (1), 409 (1), 383 (3), 308 (3), 254 (3),
226 (22), 86 (100); HR-MS(70 eV, EI): m/z: calcd for (C26H36N2O4):
440.2675, found: 440.2689.
‡
7.60, N 4.25; HR-MS(70 eV, EI): m/z: calcd for [M] : 327.1834, found:
327.1849.
Methyl (S)-3-amino-2,2-dimethyl-3-propionate hydrochloride (22): A sol-
ution of cerium ammonium nitrate (CAN) (163 mg, 0.3 mmol) in water
(0.95 mL) was added to a solution of 33 mg methyl 2,2-dimethyl-(S)-3-(2'-
methoxy-6'-methylphenyl)-amino-3-phenyl-propionate
(20c,
33 mg,
0.1 mmol) in acetonitrile (2 mL) at 08C. After vigorous stirring for 1 h, a
solution of CAN (109 mg, 0.2 mmol) in water (0.3 mL) was added and the
mixture was stirred for an additional hour at room temperature. The
mixture was then diluted with water (8 mL) and extracted with diethyl
ether (5 mL). The aqueous layer was set to pH 8 to 9 and extracted a second
time with ether (5 mL). After drying the combined organic layers over
2042
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0947-6539/00/0611-2042 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 11

Mannich Reaction
2032±2043
Na2SO4 and addition of a saturated solution of HCl in ether (2 mL), the
solvent was removed in vacuo. Colorless solid (56%); [a]2D2 ˆ ‡34.7 (c ˆ
0.21 in 1m HCl) {Lit.: [a]D23 ˆ À32.8 (c ˆ 1.1, 1n HCl) (S)-compound,[3g]
[a]2D6 ˆ ‡34.6 (c ˆ 0.17, 1m HCl) (R)-compound[3m]}; 1H NMR (250 MHz,
CDCl3): d ˆ 7.41 ± 7.50 (m, 3H; oH, pH), 7.34 ± 7.60 (m, 2H; mH), 4.54 (s,
1H; PhCHN), 3.76 (s, 3H; OCH3), 1.28 (s, 3H; CH3), 1.24 (s, 3H; CH3); MS
(70 eV, EI): m/z (%): 206 (0.02), 176 (0.06), 146 (0.31), 132 (0.75), 106 (100);
2403; b) G. Schmidt, H. Waldmann, H. Henke, M. Burkard, Chem.
Eur. J. 1996, 2, 1566 ± 1571.
[6] Parts of this work were published in prelimary form: R. Müller, H.
Goesmann, H. Waldmann, Angew. Chem. 1999, 111, 166 ± 169; Angew.
Chem. Int. Ed. 1999, 38, 184 ± 187.
[7] a) H. de Koning, W. N. Speckamp, Meth. Org. Chem. (Houben-Weyl),
4th ed., 1996, Vol. E21/b, p. 1953 ± 2010; b) W. N. Speckamp, H.
Hiemstra, Tetrahedon 1985, 41, 4367 ± 4416; c) Y. Yamamoto, T.
Nakada, H. Nemoto, J. Am. Chem. Soc. 1992, 114, 121 ± 125.
[8] K. Clauss, D. Grimm, G. Prossel, Liebigs Ann. Chem. 1974, 539 ± 560.
[9] Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC-101780 (8c) and 121696 (8h). Copies of the data can be
obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB21EZ, UK (fax: (‡44)1223-336-033; e-mail: deposit@
ccdc.cam.ac.uk)..
‡
HR-MS(70 eV, EI): m/z: calcd for [M À H2Cl] : 206.1181, found: 206.1200.
Acknowledgement
This research was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
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Received: September 1, 1999 [F2013]
Chem. Eur. J. 2000, 6, No. 11
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0947-6539/00/0611-2043 $ 17.50+.50/0
2043