Synthesis of novel chiral ligands from amino acids by the Ugi reaction

Article abstract of DOI:10.1016/S0957-4166(02)00530-X

The Ugi multi-component reaction is employed for the efficient synthesis of chiral ligands starting from amino acids and aryl aldehydes bearing a Lewis-base functionality. Tests on the products as ligands for enantioselective transition metal catalysis gave promising results in the palladium-catalyzed allylic substitution with e.e. values up to 81%.

Full text of DOI:10.1016/S0957-4166(02)00530-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1929–1936
Synthesis of novel chiral ligands from amino acids by the Ugi
reaction
Gerald Dyker,* Klaus Breitenstein and Gerald Henkel
Fachbereich 6, Institut fu¨r Synthesechemie, Gerhard-Mercator-Universita¨t Duisburg, Lotharstraße 1, D-47048 Duisburg, Germany
Received 25 July 2002; accepted 29 August 2002
Abstract—The Ugi multi-component reaction is employed for the efficient synthesis of chiral ligands starting from amino acids
and aryl aldehydes bearing a Lewis-base functionality. Tests on the products as ligands for enantioselective transition metal
catalysis gave promising results in the palladium-catalyzed allylic substitution with e.e. values up to 81%. © 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
Among the MCRs known today, the Ugi four compo-
nent reaction (U-4CR, Scheme 1), which combines an
amine, an aldehyde or ketone, a carboxylic acid and an
isocyanide to give an amino acid derivative, has gained
considerable importance in drug discovery,6 e.g. in the
synthesis of lactams,7–10 piperazines,7,11–14 benzodi-
azepinediones,12,13 other heterocycles of different ring
sizes,15–18 and bioconjugates.19,20
Since the beginning of the last decade combinatorial
chemistry and the systematic screening of compound
libraries have given major impetus to the search for
new drugs.1 Multi-component reactions (MCRs) are of
particular importance for the generation of compound
libraries, due to their exploratory power,2 their atom
economy and the convergent character of the reaction.
Thus, a given lead structure is modified and optimized
towards the desired activity. This procedure is essen-
tially the same in the search for novel ligands for
transition metal catalysis: Once a complex of a transi-
tion metal and a ligand is found to have a certain
activity, structural optimization of the ligand’s lead
structure is carried out with the aim to drive the
catalytic activity of the complex towards a maximum.
Additionally, in stereoselective catalysis the stereoselec-
tivity of the reaction is to be maximized. Combinatorial
chemistry has been employed for this type of
optimization.3–5
Most interestingly, the reaction of an amino acid with
an aldehyde and an isocyanide in a nucleophilic solvent
(e.g. methanol) results in a modification of the U-4CR,
classified as the Ugi five-center four-component
reaction (U-5C-4CR), which yields a 1,1%-iminodi-
carboxylic acid derivative21 (Scheme 2). High yields
and good diastereoselectivities are usually obtained,
making the U-5C-4CR especially attractive for the syn-
thesis of chiral multifunctionalized molecules which
might be suitable for the complexation of transition
metals.
Scheme 1. General scheme of the U-4CR.
* Corresponding author. Present address: Fakulta¨t fu¨r Chemie, Ruhr-Universita¨t Bochum, D-44780 Bochum, Germany. Tel.: +49-203-32-24551;
fax: +49-203-32-14353; e-mail: gerald.dyker@ruhr-uni-bochum.de
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00530-X

1930
G. Dyker et al. / Tetrahedron: Asymmetry 13 (2002) 1929–1936
Scheme 2. The U-5C-4CR resulting in 1,1%-iminodicarboxylic acid derivatives.
Amino acids are an attractive source of stereochemical
information and have therefore been commonly
2. Ligand synthesis
employed for the synthesis of chiral ligands,22 e.g. in
Aratani’s Schiff base ligands 123 and in the popular
PHOX ligands 2 introduced by Pfaltz,24 Helmchen25,26
and Williams.27
Since the backbone of the iminodicarboxylic acid
derivative typically contains a secondary amino group,
we decided to introduce a phosphine and a pyridine
functionality, respectively, as second donor functional-
ity for novel N,N- and P,N-ligands. To obtain ligands
capable of forming chelates with reasonable ring size,
the second donor was to be introduced in the aldehyde
component. For the first evaluation pyridine-2-alde-
hyde 3 and o-(diphenylphosphino)benzaldehyde 4,28
respectively, were condensed with L
-valine (R1=i-pro-
pyl) and tert-butyl isocyanide 5a in anhydrous
methanol at room temperature (cf. Table 1, entries 1
and 3). Good to excellent yields and moderate to high
diastereomeric excesses (de) were obtained. To study
the effect of the reaction temperature, ligand 7a was
also synthesized at low (rising from −60 to 0°C, entry 2)
and elevated temperature (100°C, entry 4). It was found
that the best yield was achieved at room temperature
(entry 3). The increased diastereoselectivity at lower
temperature was only marginal and does not justify the
prolonged reaction time and extra experimental
requirements.
However, these approaches for the synthesis of amino
acid based ligands generally represent linear syntheses
with respect to the amino acid and the inherent neces-
sity to control racemization is a serious drawback of
this concept, because detection of racemization can be
troublesome. Due to its shortness and simplicity the
U-5C-4CR represents a versatile tool for the synthesis
of chiral compounds from amino acids. It was shown to
proceed without racemization of the utilized amino
acid.21
For comparison, the sterically demanding mesityl isocy-
anide 5d, and two relatively unhindered aryl iso-
cyanides (methyl-5b, p-tolyl-5c) were tested as model
components (entries 5–7). In all cases the U-5C-4CR
was indeed successful, confirming that the correspond-
For these reasons we tested the U-5C-4CR for the
synthesis of ligands to be used in enantioselective tran-
sition metal catalysis.
Table 1. Results of ligand syntheses
Entry
Compound no. Aldehyde R2–CHO Isocyanide R3–NC
Time (h)
Temperature (°C)
Yield (%)
D.e.a (%)
1
2
3
4
5
6
7
6
7a
7a
7a
7b
7c
7d
3
4
4
4
4
4
4
5a
5a
5a
5a
5b
5c
5d
26
190
45
18
50
20
67
70
90
77
73
39
60
41
84
81
78
82
76
76
−60 to 0
20
100
20
20
20
74
74
a Determined by 1H NMR spectroscopy

G. Dyker et al. / Tetrahedron: Asymmetry 13 (2002) 1929–1936
1931
ing solid-phase synthesis of immobilized ligands
should be possible, if an isocyanide-functionalized
solid phase is employed.
3) is known to proceed stereoselectively in the presence
of chiral P,N-ligands (e.g. PHOX ligands), hence this
reaction was employed for testing the chirality transfer
properties of the ligands. 1,3-Diphenylpropenylacetate
933 was utilized as the substrate.
The absolute configuration of the newly formed
stereogenic center for the main diastereomer of ligand
7a was analyzed by X-ray crystallography. Since most
of the ligands synthesized are sticky oils or glassy
solids it was necessary to oxidize 7a to the correspond-
ing phosphine oxide 8a (H2O2 in acetone) in order to
obtain suitable crystals. The newly formed stereogenic
center proved to have the R configuration (Fig. 1),29
which contradicts the results reported by Ugi,21,22 but
is in agreement with the findings of Kim;15 therefore a
general mechanistic interpretation of the stereochemi-
cal course of the reaction requires more experimental
investigation.
The results obtained are shown in Table 2. Although
N,N-ligands (e.g. aza-semicorrins introduced by
Pfaltz35 and the diaziridine introduced by Andersson
and Tanner36) proved to be useful in the Pd-catalyzed
allylic substitution reaction, the N,N-ligand 6 gave a
virtually inactive catalyst with Pd(OAc)2 (entry 1). In
contrast, catalysts formed with the P,N-ligands 7
showed moderate to very good activities: from the
yields obtained it can be concluded that ligands bear-
ing alkyl substituents as R3 (Table 2, entries 2 and 3)
give more active catalysts than those with aromatic
substituents (entries 4 and 5). Furthermore, consider-
ing the enantiomeric excess achieved, it becomes clear,
that a bulky alkyl substituent results in significantly
higher enantioselectivity (entry 2). Therefore, further
optimization was carried out with the tert-butyl substi-
tuted ligand 7a.
3. Ligand testing in transition metal catalysis
The Ni-catalyzed Michael addition reaction is known
to proceed stereoselectively in the presence of N,N-lig-
ands.30,31 However, no catalytic activity was observed
with neither ligand 6 nor 7a.
The Pd-catalyzed allylic substitution reaction of an
allylic acetate functionality by a malonate26,32 (Scheme
Fuji et al. reported on the significant influence of the
base employed in the reaction with the BINOL based
ligand MeO–MOP, 11.37 Hence, we investigated the
effect of different bases on the selectivity of the model
reaction (Table 3).
Scheme 3. Employed test reaction for ligand evaluation: Pd-
Figure 1. X-Ray crystal structure of 8a.
catalyzed allylic substitution reaction.
Table 2. Results of the Pd-catalyzed allylic substitution reaction with a variety of ligands
Entry
Ligand (% d.e.)
Reaction time (h)
Yield 10 (%)
E.e. (configuration)a (%)
1
2
3
4
5
6 (41)
66
23
45
115
90
10
91
86
28
70
Not determined
75 (R)
2 (S)
37 (R)
33 (R)
7a (81)
7b (82)
7c (76)
7d (76)
Reaction conditions: 5 mol% Pd(OAc)2, 20 mol% ligand, N,O-bis(trimethylsilyl)acetamide (BSA)/KOAc as base, THF as solvent, room
temperature.
a Determined by 1H NMR spectroscopy with Eu((+)-hfc)3 and comparison of specific rotation value with literature data.34

1932
G. Dyker et al. / Tetrahedron: Asymmetry 13 (2002) 1929–1936
Table 3. Results of the Pd-catalyzed allylic substitution reaction with ligand 7a and different bases
Entry
Ligand (% d.e.)
Base
Yield 10 (%)
E.e. (configuration) (%)
1
2
3
7a (84)
7a (81)
7a (84)
NaH
BSA/KOAc
BSA/CsOAc
99
91
94
64 (R)
75 (R)
70 (R)
Reaction conditions as described for Table 2.
Our findings are in accord with the results reported by
Fuji et al.: the utilization of N,O-bis(trimethylsilyl)-
acetamide (BSA) (entries 2 and 3) leads to higher e.e.
than NaH (entry 1). However, the catalysts formed
with the ligands presented here are influenced much less
by the nature of the base.
rigidity to varying reaction conditions, which may be
advantageous.
As the U-5C-4CR usually yields
a mixture of
diastereomers, we aimed to gain knowledge on the way
each diastereomer affects the catalytic reaction. Ligand
7a (R,S-7a) was therefore employed with various
Whereas ligands like PHOX 2 or MeO–MOP 11 con-
tain only few polar functional groups and hence are
rather non-polar, our ligands contain very polar groups
that are capable of hydrogen bonding. Therefore, we
were interested to elaborate on the influence of the
solvent on the catalyst formed. Thus, three solvents
were tested: THF (polar, complexing), dichloromethane
(polar, not complexing), and toluene (unpolar, not
complexing). The results are shown in Table 4.
diastereomeric excess; from
a
2:1 mixture of
diastereomers to almost pure (R,S)-isomer (the major
isomer obtained from the U-5C-4CR). The results
(Table 5) indicate, that with the major isomer a more
selective catalyst is formed (entry 1): despite the pro-
longed reaction time the yield obtained with the 2:1
mixture of diastereomers (entry 3) is lower and
decreased enantiomeric excess is observed.
In both polar solvents THF and DCM, the reactions
proceed in high yields and with good enantioselectivi-
ties (entries 1 and 2). However, the time to complete the
reaction is significantly prolonged in neat dichloro-
methane (entry 2). Surprisingly, a mixture of both polar
solvents gives a quantitative yield in a shorter reaction
time (entry 3), with similar enantioselectivity to the
single solvent systems. Obviously, a certain amount of
an additional complexing agent (here: solvent) enhances
the reactivity of the complexes formed. Toluene is
clearly unsuitable as a solvent in this case, with virtu-
ally no catalysis taking place (entry 4).
4. Summary
In summary, we have shown that the Ugi reaction is
suitable for the synthesis of chiral ligands for transition
metal catalysis. Incorporating a phosphine functionality
yielded novel P,N-ligands, which were successfully
tested in the Pd-catalyzed allylic substitution reaction.
The major advantage of this approach is the immediate
utilization of amino acids as a source of stereochemical
information. Since the Ugi reaction is excellently suited
to the synthesis of compound libraries by application of
combinatorial principles, further optimization of the
ligand structure could be driven forward in a systematic
manner by screening of ligand libraries.
Since the enantioselectivity of the catalytic reaction is
essentially unaffected by the solvent, the ligands show
Table 4. Results of the Pd-catalyzed allylic substitution reaction with ligand 7a in different solvents
Entry
Ligand (% d.e.)
Solvent
Reaction time (h)
Yield 10 (%)
E.e. (configuration) (%)
1
2
3
4
7a (81)
7a (81)
7a (81)
7a (81)
THF
CH2Cl2
CH2Cl2/THF 11:2*
Toluene
23
42
17
93
91
92
100
8
75 (R)
73 (R)
76 (R)
Not determined
Reaction conditions as described for Table 2.
* Volume proportions.
Table 5. Results of the Pd-catalyzed allylic substitution reaction with ligand 7a at varying excesses of the (R,S)-diastereomer
Entry
Ligand (% d.e.)
Reaction time (h)
Yield 10 (%)
E.e. (configuration) (%)
D1
D2
D3
7a (\95)
7a (81)
7a (53)
24
23
42
92
91
82
81 (R)
75 (R)
69 (R)
Other conditions as described for Table 2.

G. Dyker et al. / Tetrahedron: Asymmetry 13 (2002) 1929–1936
1933
5. Experimental
7.39; N, 5.55; found C, 71.20; H, 7.33; N, 5.48; IR
(film): w=3416 cm−1 (w), 3337 (w), 3054 (w), 2964 (s),
2873 (w), 1735 (s), 1678 (s), 1585 (w), 1510 (s), 1477
(m), 1451 (m), 1432 (s), 1390 (w), 1364 (m), 1303 (w),
1266 (m), 1224 (m), 1198 (s), 1153 (m), 1119 (w), 1092
(w), 1070 (w), 997 (w), 745 (s), 698 (s); UV–vis (acetoni-
trile): umax (log m)=192 nm (4.90), 194 (4.91), 196
(4.90), 265 (3.96); 1H NMR: l=0.82 (d, J=6.8 Hz, 3H,
(CH3)2CH), 0.87 (d, J=6.8 Hz, 3H, (CH3)2CH), 1.08 (s,
9H, (CH3)3C), 1.83 (‘sext’, ‘J’=6.8 Hz, 1H,
NMR spectra were recorded at 500.1 MHz proton
resonance frequency in CDCl3 unless otherwise stated.
Melting points are uncorrected. Diastereomeric excesses
were determined by 1H NMR spectroscopy, enan-
1
tiomeric excesses were determined by H NMR spec-
troscopy with Eu((+)-hfc)3 (25 mol%) and comparison
of specific rotation values with the literature data.33
Ligand syntheses and catalyses are carried out in dry
solvents under argon. Methanol was dried by refluxing
with magnesium turnings and distilled, dichloro-
methane was dried by refluxing with CaH2 and subse-
quent distillation, toluene and THF were distilled from
Na/benzophenone prior to use. Isocyanides were syn-
thesized according to literature procedures.38 The sub-
strate 9 for the Pd-catalyzed allylic substitution reaction
was synthesized according to Bosnich.39
(CH3)2CH), 2.69 (b, 1H, NH), 2.78 (d, J=5.6 Hz, 1H,
4
CHCOOCH3), 3.62 (s, 3H, COOCH3), 5.22 (d, JH,P
=
9.8 Hz, 1H, CHCONH), 5.59 (bs, 1H, CONH), 7.00
(ddd, J=7.2, 3.9, 1.2 Hz, 1H, Ar), 7.17–7.21 (m, 3H,
Ar), 7.27–7.39 (m, 9H, Ar), 7.66 (ddd, J=7.8, 4.4, 1.2
Hz, 1H, Ar); 13C NMR: l=18.33 (q, (CH3)2CH), 19.18
(q, (CH3)2CH), 28.34 (q, (CH3)3C), 31.47 (d,
(CH3)2CH), 50.88 (s, (CH3)3C), 51.46/51.48 (2 d,
COOCH3), 61.73 (dd, 3JC,P=27.0 Hz, CHCONH),
5.1. General procedure for synthesis of ligands by
U-5C-4CR
64.10 (d, CHCOOCH3), 127.95 (d, Ar), 128.16 (ddC,P,
3
3JC,P=5.0 Hz, Ar), 128.50 (ddC,P, JC,P=5.5 Hz, Ar),
3
128.50 (d, Ar), 128.82 (ddC,P, JC,P=7.5 Hz, Ar), 129.08
2
The aldehyde (2 mmol) and
L
-Valine (2 mmol) were
(d, Ar), 129.84 (d, Ar), 133.13 (ddC,P, JC,P=19.0 Hz,
suspended in dry methanol (15 ml) in a screw-cap
vessel. A solution of the isocyanide 5 (2.1 mmol) in
methanol (5 ml) was added and the reaction mixture
was stirred for the time indicated in Table 1. The
solvent was evaporated and the ligand is isolated from
the residue by flash chromatography.
Ar), 134.02 (ddC,P
C,P=1.5 Hz, Ar), 135.85 (sdC,P
,
2JC,P=19.9 Hz, Ar), 134.37 (dd,
J
,
2JC,P=9.5 Hz, Ar),
2
3
136.31 (sdC,P, JC,P=12.5 Hz, Ar), 136.87 (sdC,P, JC,P
=
3
10.5 Hz, Ar), 144.80 (sdC,P, JC,P=25.4 Hz, Ar), 170.66
(s, CONH), 175.09 (s, COOCH3); 31P NMR: l=
−19.46; MS (70 eV, 150°C); m/z (%): 504 (2) [M+], 445
(3), 404 (100), 317 (29), 288 (20), 261 (20), 183 (29).
5.1.1. (2S,1%RS)-2-[1%-N-tert-Butylcarbamoyl-(pyridine-
2-yl)-methyl]amino-3-methylbutanoic acid methyl ester,
6. Rf (MTBE/PE 1:1)=0.21. Yield 433 mg (1.35 mmol,
67%), yellow oil, d.e.=41%; C17H27N3O3 (321.42): calcd
C, 63.53; H, 8.45; N, 13.01; found C, 63.50; H, 8.47; N,
13.07; IR (film): w=3333 cm−1 (m), 3057 (w), 2964 (s),
2875 (m), 1735 (s), 1675 (s), 1591 (s), 1569 (m), 1512 (s),
1467 (s), 1431 (s), 1390 (s), 1363 (s), 1270 (s), 1227 (s),
1199 (s), 1154 (s), 1096 (w), 1049 (m), 998 (m), 929 (w),
905 (w), 821 (w), 768 (m), 752 (s), 625 (m); UV–vis
(acetonitrile): umax (log m)=208 nm (3.91, sh), 255 nm
5.1.3.
(2S,1%RS)-2-[N-(1%-N-Methylcarbamoyl)-(o-
diphenylphosphino)-benzyl)]amino-3-methylbutanoic acid
methyl ester, 7b. Rf (MTBE/PE 2:1)=0.39. Yield 670
mg (1.45 mmol, 73%) colorless glassy solid, mp 40–
42°C, d.e.=82%; C27H31N2O3P (462.53): calcd C, 70.11;
H, 6.76; N, 6.06; found C, 69.62; H, 6.94; N, 6.02
(correction by 4.5 mol% CH2Cl2 (also detected be
NMR and MS) C, 69.63; H, 6.72; N, 6.00, correct
elemental analysis was obtained for the corresponding
phosphine oxide; IR (film): w=3426 cm−1 (w), 3343 (w),
3053 (w), 2961 (m), 2873 (w), 1731 (s), 1676 (s), 1585
(w), 1518 (m), 1462 (m), 1432 (s), 1410 (w), 1386 (w),
1366 (w), 1307 (w), 1246 (m), 1200 (s), 1153 (m), 1092
(w), 1070 (w), 998 (w), 916 (w), 853 (w), 746 (s), 698 (s);
UV–vis (acetonitrile): umax (log m)=192 nm (4.83), 194
1
(3.51, sh), 261 (3.56), 268 (3.46); H NMR: l=1.05 (d,
J=6.8 Hz, 3H, (CH3)2CH), 1.07 (d, J=6.8 Hz, 3H,
(CH3)2CH), 1.33 (s, 9H, (CH3)3C), 2.08 (m, 1H,
(CH3)2CH), 3.04 (d, J=5.6 Hz, 1H, CHCOOCH3),
3.61 (s, 3H, COOCH3), 3.64 (b, 1H, NH), 4.05 (s, 1H,
CHCONH), 7.19 (m, 1H, 4-H), 7.55 (m, 1H, 2-H), 7.59
(b, 1H, CONH), 7.63 (m, 1H, 3-H), 8.55 (ddd, J=4.9,
1.7, 0.9 Hz, 5-H); 13C NMR: l=18.31 (q, (CH3)2CH),
20.03 (q, (CH3)2CH), 28.64 (q, (CH3)3C), 31.51 (d,
(CH3)2CH), 50.59 (s, (CH3)3C), 51.58 (q, COOCH3),
66.65 (d, CHCOOCH3 or CHCONH), 66.73 (d,
CHCOOCH3 or CHCONH), 122.56 (d, C-2 or C-4),
122.63 (C-2 or C-4), 136.42 (d, C-3), 148.63 (d, C-5),
156.65 (s, C-1), 170.62 (s, CONH), 174.85 (s,
COOCH3); MS (70 eV, 60°C); m/z (%): 321 (1) [M+],
221 (100), 161 (46), 107 (66), 58 (59).
1
(4.87), 197 (4.87), 226 (4.26, sh), 266 (3.81); H NMR:
l=0.83 (d, J=6.8 Hz, 3H, (CH3)2CH), 0.88 (d, J=6.8
Hz, 3H, (CH3)2CH), 1.86 (‘sext’, ‘J’=6.7 Hz, 1H,
(CH3)2CH), 2.45 (d, J=4.8 Hz, 3H, CONCH3), 2.77 (b,
1H, NH), 2.80 (d, J=5.7 Hz, 1H, CHCOOCH3), 3.64
(s, 3H, COOCH3), 5.22 (d, 4JH,P=9.9 Hz, 1H,
CHCONH), 5.45 (bs, 1H, CONH), 6.99 (ddd, J=7.7,
4.0, 1.0 Hz, Ar), 7.19–7.24 (m, 2H, Ar), 7.30–7.39 (m,
9H, Ar), 7.66 (ddd, J=7.8, 4.4, 1.2 Hz, 1H, Ar); 13C
NMR: l=18.43 (q, (CH3)2CH), 19.31 (q, (CH3)2CH),
26.14 (q, CONCH3), 31.51 (d, (CH3)2CH), 51.64/51.65
(2 d, COOCH3), 61.41 (dd, 3JC,P=26.4 Hz,
CHCONH), 64.17 (d, CHCOOCH3), 128.17 (d, Ar),
5.1.2.
(2S,1%RS)-2-[N-(1%-N-tert-Butylcarbamoyl)-(o-
diphenylphosphino)-benzyl)]amino-3-methylbutanoic acid
methyl ester, 7a. Rf (MTBE/PE 1:4)=0.25. Yield 908
mg (1.8 mmol, 90%), colorless crystals, mp 104–106°C,
d.e.=81%; C30H37N2O3P (504.61): calcd C, 71.41; H,
128.46 (ddC,P, JC,P=5.0 Hz, Ar), 128.63 (ddC,P, JC,P
9.0 Hz, Ar), 128.65 (d, Ar), 128.84 (ddC,P, JC,P=7.5 Hz,
Ar), 129.25 (d, Ar), 129.86 (d, Ar), 133.36 (ddC,P
C,P=19.5 Hz, Ar), 134.15 (d, Ar), 134.37 (ddC,P, JC,P
=
,
=
J

1934
G. Dyker et al. / Tetrahedron: Asymmetry 13 (2002) 1929–1936
2
20.4 Hz, Ar), 135.89 (sdC,P, JC,P=9.5 Hz, Ar), 136.49
11H, Ar), 7.41 (td, J=7.6, 1.3 Hz, 1H, Ar), 7.78 (dd,
J=6.9, 4.4 Hz, 1H, Ar); 13C NMR: l=18.07 (q, Ar-o-
CH3), 18.30 (q, (CH3)2CH), 19.30 (q, (CH3)2CH), 20.88
(q, Ar-p-CH3), 31.50 (d, (CH3)2CH), 51.61 (q,
(sdC,P
,
2JC,P=10.0 Hz, Ar), 136.79 (sdC,P
,
3JC,P=13.5
3
Hz, Ar), 144.06 (sdC,P, JC,P=24.4 Hz, Ar), 171.93 (s,
CONH), 175.19 (s, COOCH3); 31P NMR: l=−18.55;
MS (70 eV, 170°C); m/z (%): 462 (10) [M+], 404 (100),
333 (22), 306 (37), 291 (27), 275 (25).
COOCH3), 61.43 (ddC,P,
3JC,P=25.4 Hz, CHCON),
64.09 (d, CHCOOCH3), 128.32 (d, Ar), 128.64 (d, Ar),
3
128.70 (ddC,P, JC,P=6.5 Hz, Ar), 128.84 (d, Ar), 128.89
3
5.1.4.
(2S,1%RS)-2-[N-(1%-N-p-Tolylcarbamoyl)(o-
(ddC,P, JC,P=6.0 Hz, Ar), 129.27 (d, Ar), 129.85 (d,
2
diphenylphosphino)benzyl)]amino-3-methylbutanoic acid
methyl ester, 7c. Rf (MTBE/PE 1:4)=0.30. Yield 417
mg (0.77 mmol, 39%) yellow oil, d.e.=76%;
C33H35N2O3P (538.63): calcd C, 73.59; H, 6.55; N, 5.20;
found C, 73.47; H, 6.63; N, 5.02; IR (film): w=3395
cm−1 (w), 3321 (w), 3053 (w), 2961 (m), 2873 (w), 1733
(s), 1690 (s), 1594 (m), 1520 (s), 1478 (m), 1459 (m),
1432 (s), 1403 (m), 1367 (w), 1312 (m), 1296 (m), 1242
(m), 1200 (m), 1182 (m), 1151 (m), 1122 (w), 1092 (w),
1027 (w), 997 (w), 910 (w), 815 (m), 745 (s), 697 (s), 647
(w); UV–vis (acetonitrile): umax (log m)=194 nm (4.95),
Ar), 130.87 (s, Ar), 133.48 (ddC,P, JC,P=18.9 Hz, Ar),
2
134.16 (dd, JC,P=20.0 Hz, Ar), 134.21 (d, Ar), 135.03
1
(s, Ar), 135.64 (sdC,P, JC,P=9.0 Hz, Ar), 136.30 (sdC,P
,
1JC,P=8.0 Hz, Ar), 136.39 (sdC,P, JC,P=11.0 Hz, Ar),
136.52 (s, Ar), 144.46 (sdC,P, 1JC,P=24.9 Hz, Ar), 169.95
(s, CONH), 174.99 (s, COOCH3); 31P NMR: l=−
1
1
17.95; H NMR (DMSO-D6): l=0.70 (d, J=6.8 Hz,
3H, (CH3)2CH), 0.76 (d, J=6.8 Hz, 3H, (CH3)2CH),
1.76 (‘sext’, ‘J’=6.7 Hz, 1H, (CH3)2CH), 1.94 (s, 6H,
Ar-o-CH3), 2.19 (s, 3H, Ar-p-CH3), 2.79 (dd, J=9.4,
5.2 Hz, 1H, CHCOOCH3), 2.87 (dd, J=9.5, 5.0 Hz,
1H, NH), 3.51 (s, 3H, COOCH3), 5.44 (dd, J=9.7, 4.8
Hz, 1H, 6.82 (s, 2H, Ar), 6.99 (ddd, J=7.8, 3.8, 1.3 Hz,
1H, Ar), 7.15–7.48 (m, 12H, Ar), 7.72 (ddd, J=7.8, 4.4,
1.2 Hz, 1H, Ar), 8.66 (s, 1H, CONH); 13C NMR
(DMSO-D6): l=18.00 (q, (CH3)2CH), 18.35 (q,
(CH3)2CH), 19.03 (q, Ar-o-CH3), 20.64 (q, Ar-p-CH3),
1
197 (4.96), 199 (4.95), 201 (4.94), 252 (4.32); H NMR:
l=0.84 (d, J=6.8 Hz, 3H, (CH3)2CH), 0.86 (d, J=6.8
Hz, 3H, (CH3)2CH), 1.86 (sepd, J=6.8, 5.5 Hz, 1H,
(CH3)2CH), 2.26 (s, 3H, tolyl-CH3), 2.65 (b, 1H, NH),
2.90 (d, J=5.5 Hz, 1H, CHCOOCH3), 3.60 (s, 3H,
COOCH3), 5.34 (d, 4JC,P=9.1 Hz, 1H, CHCONH),
6.98–7.04 (m, 3H, Ar), 7.13–7.18 (m, 2H, Ar), 7.19–7.27
(m, 3H, Ar), 7.28–7.40 (m, 9H, Ar), 7.66 (ddd, J=7.8,
4.3, 1.2 Hz, 1H, Ar), 8.10 (b, 1H, CONH); 13C NMR:
l=18.35 (q, (CH3)2CH), 19.20 (q, (CH3)2CH), 20.84
(q, tolyl-CH3), 31.53 (d, (CH3)2CH), 51.71 (q,
COOCH3), 62.63 (ddC,P, J=24.9 Hz, CHCON), 64.56
(d, CHCOOCH3), 119.40 (d, Ar), 128.37 (d, Ar), 128.70
31.16 (d, (CH3)2CH), 51.56 (q, COOCH3), 62.04 (ddC,P
,
3JC,P=26.4 Hz, CHCON), 64.07 (d, CHCOOCH3),
2
128.10 (ddC,P, JC,P=5.5 Hz, Ar), 128.22 (d, Ar), 128.35
3
(d, Ar), 128.70 (ddC,P, JC,P=6.5 Hz, Ar), 128.75 (d,
3
Ar), 128.82 (ddC,P, JC,P=6.0 Hz, Ar), 128.84 (d, Ar),
2
129.78 (d, Ar), 132.23 (s, Ar), 133.12 (ddC,P, JC,P=19.0
2
Hz, Ar), 133.40 (ddC,P, JC,P=19.0 Hz, Ar), 134.70 (d,
(ddC,P, 3JC,P=6.5 Hz, Ar), 128.84 (d, Ar), 128.97 (ddC,P
,
Ar), 135.17 (s, Ar), 135.67 (s, Ar), 136.39 (sdC,P, JC,P
=
1
3JC,P=7.0 Hz, Ar), 129.22 (d, Ar), 129.22 (d, Ar),
13.5 Hz, Ar), 136.92 (sdC,P, JC,P=11.0 Hz, Ar), 137.15
1
130.10 (d, Ar), 133.48 (ddC,P
133.47 (s, Ar), 134.04 (ddC,P
,
,
2JC,P=19.0 Hz, Ar),
(sdC,P, ,
1JC,P=11.0 Hz, Ar), 145.00 (sdC,P 1JC,P=26.4
2JC,P=20.0 Hz, Ar),
Hz, Ar), 169.92 (s, CONH), 174.31 (s, COOCH3); 31P
NMR (DMSO-D6): l=−18.98; MS (70 eV, 205°C); m/z
(%): 567 (4) [M++1], 566 (9) [M+], 435 (18), 404 (100),
306 (30), 292 (20), 291 (20), 183 (11), 165 (10).
1
134.59 (d, Ar), 135.26 (s, Ar), 125.75 (sdC,P, JC,P=9.0
Hz, Ar), 136.20 (sdC,P
,
1JC,P=12.0 Hz, Ar), 136.31
1
1
(sdC,P, JC,P=9.5 Hz, Ar), 144.26 (sdC,P, JC,P=25.4 Hz,
Ar), 169.68 (s, CONH), 174.92 (COOCH3); 31P NMR:
l=−18.16; MS (70 eV, 170°C); m/z (%): 538 (12) [M+],
431 (14), 404 (100), 306 (30), 288 (23), 183 (25), 165
(18).
5.2. General procedure for the Pd-catalyzed allylic
substitution reaction
Catalyst solution: Pd(OAc)2 (11.2 mg (49.9 mmol, 5
mol%) and the respective ligand (200 mmol, 4 equiv.)
were dissolved in the solvent (3 ml) in a vessel fitted
with a septum. After 10 min a solution of 1,3-diphenyl-
prop-2-en-1-yl acetic acid ester 9 (253 mg, 1.0 mmol) in
solvent (2 ml) was added. Dimethyl malonate (212 mg,
1.60 mmol, 1.6 equiv.) and the respective base (cf.
Table 3) were stirred in solvent (4 ml). The catalyst
solution was added after 25 min and the mixture was
stirred for the time indicated in Tables 2–5. The mix-
ture was then hydrolyzed with phosphate buffer (pH 7,
10 ml), the phases are separated, the organic phase
dried with Na2SO4, evaporated and separated into its
components by flash chromatography.
5.1.5. (2S,1%RS)-2-[N-(1%-N-2,4,6-Trimethylphenylcar-
bamoyl)-(o-diphenylphosphino)-benzyl)]amino-3-methyl-
butanoic acid methyl ester, 7d. Rf (MTBE/PE
1:4)=0.28. Yield 680 mg (1.20 mmol, 60%), yellow oil,
d.e.=76%; C35H39N2O3P (566.68): calcd C, 74.18; H,
6.94; N, 4.94; found C, 74.15; H, 6.98; N, 4.80; IR
(film): w=3385 cm−1 (w), 3329 (w), 3053 (w), 2959 (m),
2872 (w), 1733 (w), 1691 (s), 1609 (w), 1585 (w), 1491
(s), 1433 (s), 1384 (w), 1366 (w), 1309 (w), 1236 (m),
1198 (m), 1155 (m), 1092 (w), 1027 (w), 998 (w), 851
(w), 745 (s), 698 (s); UV–vis (acetonitrile): umax (log m)=
192 nm (5.02), 194 (5.06), 196 (5.07), 199 (5.05), 265
(3.99); 1H NMR: l=0.83 (d, J=6.8 Hz, 3H,
(CH3)2CH), 0.87 (d, J=6.8 Hz, 3H, (CH3)2CH), 1.88 (s,
7H, Ar-o-CH3 and (CH3)2CH), 2.21 (s, 3H, Ar-p-CH3),
2.82 (d, J=5.4 Hz, 1H, CHCOOCH3), 2.90 (b, 1H,
NH), 3.61 (s, 3H, COOCH3), 5.44 (d, J=9.3 Hz, 1H,
CHCONH), 6.77 (s, 2H, Ar), 6.96 (b, 1H, CONH),
6.99 (ddd, J=7.7, 4.0, 1.3 Hz, 1H, Ar), 7.19–7.38 (m,
5.3. (2S,1%RS)-2-[N-(1%-N-tert-Butylcarbamoyl)-(o-
diphenylphosphinoyl)-benzyl)]amino-3-methylbutanoic
acid methyl ester, 8a
A solution of 7a (252 mg, 0.5 mmol) in acetone (20 ml)

G. Dyker et al. / Tetrahedron: Asymmetry 13 (2002) 1929–1936
1935
was stirred for 50 min with H2O2 (1 ml, 30%). After
evaporation of the solvent the residue was dissolved in
dichloromethane and dried with Na2SO4. Removal of
the solvent and drying under high vacuum afforded 8a
as a colorless oil (259 mg, 0.5 mmol, 100%). Crystals of
J=6.7 Hz, 3H, (CH3)2CH), 0.70 (d, J=6.9 Hz, 3H,
(CH3)2CH), 1.60 (‘sext’, ‘J’=6.8 Hz, 1H, (CH3)2CH),
2.07 (d, J=5.1 Hz, 1H, CHCOOCH3), 2.74 (d, J=4.7
Hz, 3H, CONCH3), 3.10 (b, 1H, NH), 3.49 (s, 3H,
COOCH3), 4.87 (s, 1H, CHCONH), 6.91 (ddd, J=
14.3, 7.8, 1.1 Hz, 1H, Ar), 7.19 (tdd, J=7.5, 2.5, 1.3
Hz, 1H, Ar), 7.45–7.65 (m, 11H, Ar), 7.96 (ddd, J=7.9,
4.2, 1.0 Hz, 1H, Ar), 8.93 (d, J=4.4 Hz, 1H, CONH);
13C NMR: l=18.03 (q, (CH3)2CH), 19.77 (q,
(CH3)2CH), 26.32 (q, CONCH3), 31.21 (d, (CH3)2CH),
1
the major diastereomer (confirmed by H NMR) suit-
able for X-ray crystal analysis are obtained by recrys-
tallization from Et2O/PE 1:3. Rf (MTBE)=0.71, mp
136–138°C; C30H37N2O4P (520.61): calcd C, 69.21; H,
7.16; N, 5.38; found C, 69.10; H, 7.22; N, 5.30; IR
(film): w=3259 cm−1 (w), 3226 (m), 3063 (m), 2963 (s),
2873 (w), 1732 (s), 1678 (s), 1566 (m), 1437 (s), 1388
(w), 1363 (m), 1304 (m), 1259 (w), 1227 (m), 1173 (s),
1119 (s), 1071 (w), 998 (w), 749 (m), 723 (s), 696 (s), 669
(w).
51.32 (q, COOCH3), 60.95 (ddC,P
CHCONH), 65.08 (d, CHCOOCH3), 126.66 (ddC,P
,
3JC,P=5.5 Hz,
,
3
3JC,P=13.0 Hz, Ar), 128.70 (ddC,P, JC,P=12.5 Hz, Ar),
129.19 (sdC,P
,
1JC,P=101.2 Hz, Ar), 129.00 (ddC,P
,
2
3JC,P=12.5 Hz, Ar), 130.24 (ddC,P, JC,P=10.0 Hz, Ar),
131.53 (sdC,P
, ,
1JC,P=107.2 Hz, Ar), 131.66 (ddC,P
UV–vis (acetonitrile): umax (log m)=194 nm (4.86), 196
(4.88), 198 (4.85), 201 (4.80), 224 (4.37, sh), 273 (3.35);
1H NMR: l=0.65 (d, J=6.8 Hz, 3H, (CH3)2CH), 0.69
(d, J=6.8 Hz, 3H, (CH3)2CH), 1.27 (s, 9H, (CH3)3C),
1.61 (‘b sext’, ‘J’=6.3 Hz, (CH3)2CH), 2.08 (d, J=5.0
Hz, 1H, CHCOOCH3), 3.10 (b, 1H, NH), 3.49 (s, 3H,
CHCOOCH3), 4.87 (s, 1H, CHCONH), 6.89 (ddd,
J=14.3, 7.6, 1.2 Hz, 1H, Ar), 7.18 (tdd, J=7.5, 2.5, 1.2
Hz, 1H, Ar), 7.45–7.65 (m, 11H, Ar), 7.91 (dd, J=7.9,
4.1 Hz, Ar), 8.80 (s, 1H, CONH); 13C NMR: l=18.09
(q, (CH3)2CH), 19.22 (q, (CH3)2CH), 28.55 (q,
(CH3)3C), 31.29 (d, (CH3)2CH), 50.69 (s, (CH3)3C),
2JC,P=10.0 Hz, Ar), 131.69 (sdC,P, 1JC,P=102.7 Hz, Ar),
2
4
132.28 (ddC,P, JC,P=9.5 Hz, Ar), 132.31 (ddC,P, JC,P
=
4
3.00 Hz, Ar), 132.49 (ddC,P, JC,P=3.00 Hz, Ar), 132.86
(ddC,P
,
3JC,P=13.5 Hz, Ar), 132.80 (overlapped, Ar),
147.46 (s, Ar), 172.03 (s, CONH), 174.57 (s, COOCH3);
31P NMR: l=34.87; MS (70 eV, 85°C); m/z (%): 478
(3) [M+], 420 (100), 306 (45), 304 (40), 292 (33), 291
(39).
Acknowledgements
51.31 (q, COOCH3), 61.34 (ddC,P
CHCONH), 65.25 (d, CHCOOCH3), 126.43 (ddC,P
,
3JC,P=5.0 Hz,
,
Financial support by the Deutsche Forschungsgemein-
schaft and by the Fonds der chemischen Industrie is
gratefully acknowledged. K.B. thanks the German Fed-
eral State of Northrhine-Westphalia for a grant.
3JC,P=13.0 Hz, Ar), 128.88 (sdC,P, 1JC,P=101.2 Hz, Ar),
128.68 (ddC,P
,
3JC,P=12.5 Hz, Ar), 128.84 (ddC,P
,
2
3JC,P=12.0 Hz, Ar), 129.82 (ddC,P, JC,P=10.0 Hz, Ar),
131.91 (sdC,P
, ,
1JC,P=107.2 Hz, Ar), 132.15 (sdC,P
1JC,P=103.0 Hz, Ar), 131.80 (ddC,P
,
2JC,P=10.5 Hz,
2
Ar), 132.23 (ddC,P, JC,P=9.5 Hz, Ar), 132.25 (ddC,P
,
References
4JC,P=3.0 Hz, Ar), 132.63 (ddC,P, JC,P=3.0 Hz, Ar),
4
132.64 (ddC,P
,
4JC,P=3.00 Hz, Ar), 132.82 (ddC,P
,
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