Phenyltrisalanine: A new, C3-symmetric, trifunctional amino acid

Article abstract of DOI:10.1016/S0957-4166(98)00377-2

Two derivatives of phenyltrisalanine, a new, trifunctional amino acid, were synthesised in optically active forms. Two complementary techniques were employed, an HWE olefination reaction or a Heck coupling reaction, and the resulting dehydroamino acids were hydrogenated using a chiral Rh(I)-Et- DuPHOS catalyst. Phenyltrisalanine derivatives of excellent stereoisomeric purities were thus obtained.

Full text of DOI:10.1016/S0957-4166(98)00377-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3491–3496
Phenyltrisalanine: a new, C -symmetric, trifunctional amino acid
3
∗
Andreas Ritzén, Basudeb Basu, Andreas Wållberg and Torbjörn Frejd
Organic Chemistry 1, Department of Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden
Received 26 August 1998; accepted 15 September 1998
Abstract
Two derivatives of phenyltrisalanine, a new, trifunctional amino acid, were synthesised in optically active forms.
Two complementary techniques were employed, an HWE olefination reaction or a Heck coupling reaction, and
the resulting dehydroamino acids were hydrogenated using a chiral Rh(I)–Et-DuPHOS catalyst. Phenyltrisalanine
derivatives of excellent stereoisomeric purities were thus obtained. © 1998 Elsevier Science Ltd. All rights
reserved.
1. Introduction
The synthesis of novel amino acids, naturally and non-naturally occurring, has been the goal of
much research in organic chemistry. The interest in such compounds is motivated by the possibility
of incorporating them into biologically active peptides to modulate the biochemical properties of such
peptides. Moreover, amino acids have in recent years also played an important part as building blocks
1,2
in various elaborate molecular architectures, and as ligands in catalytically active metal complexes for
3
use in asymmetric catalysis.
4
We have previously synthesised various derivatives of ferrocenylene-bis-alanine, pyridine-2,6-diyl
5
6
bis-alanine, and phenylene-bis-alanine in optically active forms and with orthogonal protecting groups.
These compounds were synthesised by catalytic asymmetric hydrogenation of the corresponding unsatu-
7,8
rated derivatives, which were synthesised either by Heck coupling or Horner–Wadsworth–Emmons
HWE) olefination. In the present work we have used this methodology to synthesise the hitherto
9
(
unknown, C -symmetric amino acid (6), Scheme 1, for which we propose the name phenyltrisalanine,
3
Pta.
∗
Corresponding author. E-mail: torbjorn.frejd@orgk1.lu.se
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00377-2

3492
A. Ritzén et al. / Tetrahedron: Asymmetry 9 (1998) 3491–3496
0
0
3 4 2
Scheme 1. (a) N,N,N ,N -Tetramethylguanidine, THF, rt, 4 h, 54%; (b) NaHCO , Bu NCl, Pd(OAc) , DMF, 80°C, 24 h, 44%;
+
−
(
c) {Rh(COD)[(S,S)-Et-DuPHOS]} OTf , 40 psi H , rt, 6 h, 74–99%
2
2. Results and discussion
Both the HWE path and the Heck path were used in the synthesis of Pta 6 (Scheme 1). These two paths
are complementary with respect to which protecting groups can be introduced. Phosphonate 2 is readily
available in three steps from glyoxylic acid, but the reaction conditions limit the choice of protecting
10
groups. If other protecting groups are desired, these must be introduced by deprotection–reprotection of
. Acrylate 4, however, is readily available in three steps from serine with a number of different protecting
2
7
groups. In our experience, however, the Cbz protecting group interferes with the Heck reaction. The
HWE path would thus be the route of choice for Cbz protected derivatives. Also, the HWE condensation
typically proceeds with slightly higher yields than the Heck coupling.
The synthesis of Pta 6a by the HWE path starts with a condensation between 1,3,5-triformylbenzene
111
and 2. Recrystallisation of the thus obtained derivative 5a after chromatography substantially
increased the purity. The all-Z configuration of 5a was assigned by NOE difference spectroscopy as
follows. Irradiation of the core aromatic proton yielded a 19% enhancement of the olefinic CH proton
and a 5.6% enhancement of the NH proton. In contrast, irradiation of the CH proton gave no enhancement
of the NH proton, but a 15% enhancement of the core CH proton. Finally, irradiation of the NH proton
gave no enhancement of the CH proton, but a 5.6% enhancement of the core proton.
12
Hydrogenation of 5a using a Rh(I)–(S,S)-Et-DuPHOS catalyst gave Pta 6a in 99% isolated yield. For
stereochemical analysis, a sample of 5a was hydrogenated using an achiral Rh(I)–dppe catalyst, which
produced 6a as a ca. 1:3:3:1 mixture of stereoisomers as analysed by chiral stationary phase HPLC and
NMR spectroscopy. This is the statistically expected outcome if one assumes that the hydrogenation of
each arm is independent of the others, and that the minor diastereomer has the SSS/RRR configuration,
while the major diastereomer has the SSR/SRR configuration. Note that since 6a is C -symmetric, only
3
four distinct stereoisomers exist, although the molecule has three stereogenic centres.
1
The diastereomeric ratio of 6a could be determined with high accuracy by H NMR spectroscopy and a
dr=99.4:0.6 was found. To evaluate the enantiomeric excess, HPLC using a covalent DNBPG column was
used. All four stereoisomers were resolved on this column, but baseline separation between enantiomers

A. Ritzén et al. / Tetrahedron: Asymmetry 9 (1998) 3491–3496
3493
was only obtained for the SSS/RRR diastereomer. Only one peak was observed for nonracemically
hydrogenated 6a, thus establishing ee>98% assuming a 1% detection limit in the HPLC system. For
statistical reasons, the ee is most likely much higher than the dr, since the production of the ‘wrong’
configuration at all three centres is extremely unlikely, given the high per-centre selectivity of the catalyst.
Finally, the absolute configuration is assigned as SSS based on the selectivity of the (S,S)-Et-DuPHOS
12
ligand.
Synthesis of Pta 6b by the Heck route starts with the Pd-catalysed coupling between 1,3,5-
13
7
triiodobenzene and acrylate 4. Attempts to use the commercially available 1,3,5-tribromobenzene
were unsuccessful because of the lower reactivity of aryl bromides compared to aryl iodides. Purification
of the product 5b proved difficult. After standard chromatography and recrystallisation, 5b retained
a minor amount of an impurity. Since this impurity could not readily be removed, the mixture was
hydrogenated using the Rh(I)–(S,S)-Et-DuPHOS catalyst to produce 6b and a minor amount of another
compound, which could now be separated by chromatography. Based on NMR spectroscopy and HRMS
analysis, we assign structure 8 to this compound, and from this, structure 7 is assigned to the impurity in
the preparation of 5b.
NOE analysis of 5b was used in the same way as for 5a to assign the all-Z configuration to 5b.
Stereochemical analysis of 6b was performed as for 6a, and we found dr=98.3:1.7 and ee>98%. Although
the dr is still excellent, it is significantly lower than that of 6a. The reason for this is not clear, but it seems
likely that the protecting groups have a slight influence on the selectivity.
3. Conclusion
Two derivatives of phenyltrisalanine, Pta, a hitherto unknown, trifunctional amino acid, were synthe-
sised using two different, complementary routes. Based on the present work, it should be possible to
synthesise various derivatives of Pta, and if both routes are combined, non-C -symmetric, orthogonally
3
protected derivatives should be accessible. Applications of Pta in areas such as ligand design, molecular
recognition and design of novel molecular architectures are currently being explored in our laboratory.
4. Experimental
NMR spectra were recorded on a Bruker DRX 400 NMR spectrometer in CDCl . To reduce line broad-
3
ening resulting from slow rotation around carbamate C–N bonds, spectra were collected at 40–55°C.
1
For H experiments, residual CHCl at δ 7.27 was used as an internal standard, while the central peak
3
13
of the CDCl triplet at δ 77.23 was used for C experiments. Optical rotations were measured on a
3
Perkin–Elmer 241 polarimeter, and melting points were taken with a melting point microscope and are
uncorrected. Precoated Merck silica gel 60 F254 plates were used for TLC analysis, and retention values
(
TLC R ) are given in the same solvent as used in the respective column chromatography unless otherwise
f
stated. Stereochemical HPLC analyses were performed using a covalent DNBPG column (J. T. Baker
Inc., 250×4.6 mm; DNBPG=2,4-dinitrobenzoylphenylglycine) or a (R,R)-Whelk-O1 column (Merck,
2
50×4.6 mm). Two detectors in tandem were routinely used; one LKB 2142 refractive index detector
11 10 13 7
and one Pye Unicam ultraviolet detector at 254 nm. Compounds 1, 2,
according to literature procedures, and so was {Rh(COD)[(S,S)-Et-DuPHOS]} OTf . The (S,S)-Et-
3
and 4 were synthesised
+
− 12
DuPHOS ligand is available from Strem Chemicals.

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A. Ritzén et al. / Tetrahedron: Asymmetry 9 (1998) 3491–3496
4.1. (Z,Z,Z)-1,3,5-Tri{1-[(benzyloxycarbonyl)amino]-1-(methoxycarbonyl)ethenyl}benzene 5a
11
A suspension of 1,3,5-triformylbenzene 1 (0.49 g, 3.0 mmol) in dry THF (15 ml) was added to a
10
0
0
9
stirred solution of 2 (3.28 g, 9.9 mmol) and N,N,N ,N -tetramethylguanidine (1.24 ml, 9.9 mmol)
in dry THF (30 ml) at 0°C under N . After 4 h at rt the solvent was removed by evaporation and the
2
residue was dissolved in CH Cl (50 ml). The solution was washed with half-saturated brine (50 ml)
2
2
and saturated brine (50 ml) and was then dried over Na SO . The solution was directly loaded onto a
2
4
flash chromatography column which was eluted with CH Cl :MeOH (30:1) to afford crude 5a (R =0.32).
2
2
f
If the solvent was removed prior to flash chromatography, it proved impossible to redissolve the crude
product in CH Cl . The chromatographed material was further purified by recrystallisation from EtOAc
2
2
1
to yield pure 5a as a white, amorphous solid (1.26 g, 54%), mp 199–202°C. H NMR δ 3.84 (s, 9H), 5.08
(
s, 6H), 6.23 (br s, 3H), 7.20 (s, 3H), 7.25–7.32 (m, 15H), 7.58 (s, 3H); 13C NMR δ 52.94, 67.87, 125.75,
1
6
7
28.53, 128.57, 128.78, 130.25, 131.25, 134.85, 136.12, 153.92, 165.55. Calcd for C H N O : C
4.86, H 5.05, N 5.40, O 24.68. Found C 64.2, H 4.8, N 5.3. HRMS (FAB+) m/z calcd for C H N O :
78.2612 [M+H]. Found: 778.2630.
42 39 3 12
42
39
3
12
4.2. (Z,Z,Z)-1,3,5-Tri{1-(benzyloxycarbonyl)-1-[(tert-butyloxycarbonyl)amino]ethenyl}benzene 5b
,3,5-Triiodobenzene 313 (0.46 g, 1.0 mmol), acrylate 4 (1.0 g, 3.6 mmol), NaHCO (0.63 g, 7.5
7
1
3
mmol), Bu NCl (0.83 g, 3.0 mmol), and Pd(OAc) (22 mg, 0.10 mmol) were mixed in DMF (5 ml) in a
4
2
screwcap vial. A few crystals of hydroquinone were added to prevent polymerisation of 4, and the mixture
was freed from O by N bubbling for 5 min. The vial was sealed and heated at +80°C for 24 h. The dark
2
2
reaction mixture was allowed to cool, and was diluted with EtOAc (50 ml). The resulting mixture was
washed with water (2×50 ml) and brine (2×50 ml) and was then dried over Na SO . Evaporation of
2
4
the solvent followed by flash chromatography using heptane:EtOAc (2:1) as eluent gave crude 5b as a
yellow semisolid (0.75 g), R =0.21. Recrystallisation twice from EtOAc:heptane yielded a pale yellow
f
1
solid (0.40 g, 44%), mp 123–131°C, which contained ca. 20% (by H NMR) of an impurity of the same
1
R , probably 7 (see text). This material was used in the hydrogenation leading to 6b. H NMR δ 1.35
f
13
(
2
s, 27H), 5.29 (s, 6H), 6.26 (br s, 3H), 7.23 (s, 3H), 7.35–7.42 (m, 15H), 7.61 (s, 3H); C NMR δ
8.24, 67.83, 81.41, 125.53, 128.50, 128.63, 128.66, 128.72, 128.82, 131.32, 134.77, 135.57, 152.59,
1
65.38 (one peak at δ 128 originates from 7; it is not known which one). HRMS (FAB+) m/z calcd for
C H N O : 926.3840 [M+Na]. Found: 926.3848.
51
57
3
12
4.3. (S,S,S)-1,3,5-Tri{1-[(benzyloxycarbonyl)amino]-1-(methoxycarbonyl)ethyl}benzene 6a
+
−
12
Compound 5a (100 mg, 128 µmol) and {Rh(COD)[(S,S)-Et-DuPHOS]} OTf (3 mg) were sus-
pended in a 1:1 mixture of MeOH and EtOAc (20 ml) rigorously deoxygenated by N bubbling and
2
sonication for 15 min. This mixture was hydrogenated at 40 psi for 6 h at rt. After this time a clear
solution was obtained. The solvents were evaporated, and the residue was dissolved in EtOAc and filtered
through a short plug of silica to remove the catalyst. An equal volume of heptane was added to facilitate
crystallisation, and the solvents were removed by evaporation to yield pure 6a as a white, amorphous
2
2
solid (100 mg, 99%), mp 100–103°C, [α]D +62 (c 1.0; CHCl ). The reaction could be performed on a
3
1
.0 g scale using 10 mg of catalyst and no less than 150 ml of solvent with the same outcome as above.
The very low solubility of 5a and the low solubility of 6a necessitate the use of rather large solvent
1
volumes, and the addition of EtOAc as a co-solvent. H NMR δ 2.94–3.05 (m, 6H), 3.67 (s, 9H), 4.59 (br
q, 3H, J=6 Hz), 5.07 (d, 3H, J=12 Hz), 5.11 (d, 3H, J=12 Hz), 5.20 (br s, 3H), 6.75 (s, 3H), 7.27–7.35 (m,

A. Ritzén et al. / Tetrahedron: Asymmetry 9 (1998) 3491–3496
3495
1
1
5H); 13C NMR δ 38.45, 52.49, 55.13, 67.21, 128.36, 128.37, 128.74, 129.42, 136.64, 136.77, 155.85,
71.96. Calcd for C H N O : C 64.36; H 5.79; N 5.36; O 24.49. Found C 64.9, H 5.7, N 5.2. HRMS
42
45
3
12
(
FAB+) m/z calcd for C H N O : 784.3082 [M+H]. Found: 784.3063.
42 45 3 12
+
−
A sample of 5a was racemically hydrogenated using [Rh(COD)(dppe)] BF as catalyst to produce
4
1
6
a as a mixture of stereoisomers. The H NMR spectrum of this material was similar to that of optically
active 6a, but the diastereomers differed in the region of the aromatic core protons. Since the C3-
symmetry is broken in the SSR/SRR diastereomer, the three core protons appear as two signals with a
2
:1 area, while in the C -symmetric SSS/RRR diastereomer, these three protons appear as a singlet. The
3
chemical shifts were for the SSS/RRR diastereomer: δ 6.75 (s, 3H), and for the SSR/SRR diastereomer: δ
.74 (s, 1H), 6.78 (s, 2H). The peaks at δ 6.75 and 6.78 were almost baseline separated, and this allowed
6
a very accurate determination of the diastereomeric excess of optically active 6a: dr=99.4:0.6. For the
racemically hydrogenated 6a, the dr was found to be 1:3 SSS/RRR:SSR/SRR.
HPLC analysis (DNBPG, n-hexane:2-propanol=90:10, 1.0 ml/min) of racemically hydrogenated 6a
produced a chromatogram with four peaks with retention times min (area) 34.7 (1), 35.8 (3), 37.6 (3) and
39.7 (1). The peaks were fairly well resolved, but not baseline separated. Since the catalyst is racemic,
peaks of equal area must correspond to enantiomeric pairs. Thus, the first and last peaks correspond to one
diastereomer, and the second and third peaks correspond to the other. For statistical reasons, the minor
diastereomer should be SSS/RRR. Co-injection with optically active 6a enhanced the first eluted peak.
This was assigned the SSS configuration, based on the S preference of the (S,S)-Et-DuPHOS ligand.12
Only one peak was seen when optically active 6a was analysed. Assuming a detection limit of 1%, this
means that 6a was formed with ee>98%.
4.4. (S,S,S)-1,3,5-Tri{1-(benzyloxycarbonyl)-1-[(tert-butyloxycarbonyl)amino]ethyl}benzene 6b
+
−
Compound 5b (100 mg, 111 µmol) and {Rh(COD)[(S,S)-Et-DuPHOS]} OTf (3 mg) were dissolved
in MeOH rigorously deoxygenated by N bubbling and sonication for 15 min. This mixture was
2
hydrogenated at 40 psi for 6 h at rt. The solvent was evaporated, and the residue was dissolved in EtOAc
and filtered through a short plug of silica to remove the catalyst. TLC analysis (heptane:EtOAc=2:1)
revealed that this material was a mixture of two compounds, 6b (R =0.31) and a compound tentatively
f
assigned structure 8 (R =0.23). After flash chromatography (heptane:EtOAc=5:2) 6b (74 mg, 74%) and
f
8
(15 mg) were obtained as pure compounds.
22
For compound 6b: mp=42–44°C, [α]
+10 (c 1.0; CHCl ) (optical rotation at longer wavelengths
3
365
1
is close to zero), H NMR δ 1.41 (s, 27H), 2.89–3.00 (m, 6H), 4.52 (br s, 3H), 4.93 (br s, 3H), 5.12
d, 3H, J=12 Hz), 5.18 (d, 3H, J=12 Hz), 6.66 (s, 3H), 7.30–7.35 (m, 15H); 13C NMR δ 28.52, 38.23,
4.87, 67.22, 80.20, 128.63, 128.80, 129.37, 135.71, 136.76, 155.21, 171.71. HRMS (FAB+) m/z calcd
for C H N O : 932.4309 [M+Na]. Found: 932.4291.
(
5
51
63
3
12
1
For compound 8: mp=57–60°C, H NMR δ 1.38 (s, 36H), 2.97–3.13 (m, 8H), 4.59 (br s, 4H), 4.97
br s, 4H), 5.11–5.18 (ABq, 8H), 6.83 (br t, 2 H J≈1 Hz), 7.13 (br d, 4H, J≈1 Hz), 7.25–7.32 (m,
(
13
2
1
1
0H); C NMR δ 28.54, 38.61, 54.94, 67.31, 80.26, 127.21, 128.50, 128.61, 128.81, 129.62, 135.67,
37.18, 141.51, 155.24, 171.85. HRMS (FAB+) m/z calcd for C H N O : 1285.5937 [M+Na]. Found:
72
86
4
16
285.5952.
Stereochemical analysis of 6b was carried out as for 6a above. The chemical shifts of the aromatic core
protons were for the SSS/RRR diastereomer: δ 6.66 (s, 3H), and for the SSR/SRR diastereomer: δ 6.66
s, 1H, completely overlapped with the signal from the SSS/RRR diastereomer), 6.69 (br d, 2H, J=1.3
Hz). The dr for 6b was found to be 98.3:1.7. HPLC analysis [(R,R)-Whelk-01, n-hexane:2-propanol
0:20+0.25% HOAc, 1.0 ml/min] of a racemically hydrogenated sample gave only three peaks with
(
8

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A. Ritzén et al. / Tetrahedron: Asymmetry 9 (1998) 3491–3496
retention times min (area) 12.5 (1), 14.1 (3) and 14.9 (4). The first peak was baseline separated from the
other two, and corresponds to the SSS isomer by comparison with optically active 6b. HPLC analysis of
optically active 6b gave two peaks with the following retention times, respectively: min (area) 12.4 (98.3)
and 14.6 (1.7) (refractive index detection). This corresponds exactly to the result of the NMR analysis,
although the presence of a small amount (<1%) of the RRR isomer cannot be ruled out based on this
analysis. However, for statistical reasons, only a minute amount is expected. The ee is thus >98%.
Acknowledgements
We wish to thank the Knut and Alice Wallenberg Foundation, The Crafoord Foundation, the Royal
Physiographical Society, and the Swedish Natural Research Council for financial support and a post doc
scholarship to B.B.
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