Synthetic aromatic amino acids from a negishi cross-coupling reaction

Article abstract of DOI:10.1055/s-0029-1217124

An N,O-protected, iodinated bishomoalanine derivative, safely available from glutamic acid, reacts with aryl halides in a Negishi reaction in high yields. From the coupling product, Fmoc-protected amino acids with aromatic and heteroaromatic side chains were generated in high yields by racemization-free procedures. These monomers could be used for solid-phase peptide synthesis. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217124

PAPER
293
Synthetic Aromatic Amino Acids from a Negishi Cross-Coupling Reaction
Synthetic
Aromatic
A
m
a
ino Acidsrcel Suhartono, Angelika E. Schneider, Gerd Dürner, Michael W. Göbel*
Institut für Organische Chemie und Chemische Biologie, Goethe-Universität Frankfurt, Max-von-Laue-Str. 7, 60438 Frankfurt am Main,
Germany
Fax +49(69)79829464; E-mail: m.goebel@chemie.uni-frankfurt.de
Received 26 June 2009; revised 28 September 2009
cross-coupling reactions. Here we report on the conver-
Abstract: An N,O-protected, iodinated bishomoalanine derivative,
sion of glutamic acid into the enantiomerically pure bis-
safely available from glutamic acid, reacts with aryl halides in a
homoalaninol derivative 5. Compound 5 serves as a key
intermediate that, after halogen–zinc exchange, can be
Negishi reaction in high yields. From the coupling product, Fmoc-
protected amino acids with aromatic and heteroaromatic side chains
were generated in high yields by racemization-free procedures. transformed into a broad range of amino acid precursors
These monomers could be used for solid-phase peptide synthesis.
by Negishi cross coupling with aryl and heteroaryl ha-
lides. Similar Negishi reactions8 of iodoalanine and other
Key words: amino alcohols, chiral pool, nickel catalyst, RNA
ligand, zinc organyls
iodinated amino acid derivatives have been previously
achieved by Jackson et al.9
After the esterification of L-glutamic acid (1) with chlo-
rotrimethylsilane in methanol and Boc protection in quan-
titative yield, both ester groups were reduced under mild
conditions with lithium borohydride (Scheme 1). Lower
yields were obtained in this step using lithium aluminum
hydride. Almost no product was isolated with sodium
borohydride, even in the presence of lithium chloride. Se-
lective N,O-ketalization of aminodiol 3 with 2,2-
dimethoxypropane then formed the oxazolidine moiety of
4,10 which is thermodynamically favored over acetonides
with medium-sized rings. To obtain building block 5, the
remaining primary alcohol was converted into the alkyl
halide with iodine/triphenylphosphine.
RNA with its various secondary and tertiary structures of-
fers binding sites for antibiotics, proteins, and small mol-
ecules.1 It can, thus, be considered an interesting drug
target. Recently, we reported on basic tripeptides that bind
to the TAR element of HIV-1.2 The association with TAR
blocks the Tat/TAR complex, an important molecular
switch regulating transcription efficacy in HIV,3 and
thereby inhibits the replication of HIV in cell culture ex-
periments.2
Complex formation between RNA and ligands is gov-
erned by hydrogen bonds, Coulomb forces, and stacking
interactions. If peptide ligands are considered, the main
contribution to stacking comes from aromatic amino acids
and thus is limited to His, Phe, Trp, and Tyr. Our concept
to expand the potency of peptidic RNA ligands was to
start from a broader range of building blocks capable of
stacking with nucleobases. Towards this aim we are inter-
ested in the preparation of artificial amino acids with aro-
matic moieties.
Zinc organyl 6 (Scheme 2) was prepared from 5 with io-
dine-activated zinc powder.11,12 The cross-coupling step
of reagent 6 and aryl bromides proved troublesome at the
beginning when palladium catalysts were used. The key to
success was to apply NiCl2(PPh3)2 instead. Finally, varia-
tion of the solvent, reaction time, and temperature led to
the optimal conditions (DMF, 80 °C, 3 h) producing com-
pounds 7a–g at gram scale.12 The use of aryl iodides,
which was tested exemplarily for 2-iodo-6-methoxynaph-
thalene, did not increase the yield significantly.
For the synthesis of non-natural amino acids various
methods exist.4,5 Some convert prochiral starting materi-
als enantioselectively into the amino acid precursor,
which is most elegant in a formal sense. This approach re-
quires, on the other hand, the optical purity to be verified
for each new amino acid and, if necessary, the level of
enantiomeric excess to be enriched in a further purifica-
tion step.
The quinoline derivative 10 represents an exception.
Here, the desired Negishi product 7h was not formed at
all. Instead, almost quantitative homocoupling of the aro-
matic system was observed (Scheme 2).
With cross-coupling products 7 made available, just a few
steps were required to obtain the corresponding a-amino
acids 9. At first, the protecting groups were removed si-
multaneously under acidic conditions. The amino residue
was then reprotected with N-{[(9-fluorenylmethoxy)car-
bonyl]oxy}succinimide (Fmoc-OSu) to give 8. Oxidation
of the hydroxy group with pyridinium dichromate in N,N-
dimethylformamide completed the synthesis of amino ac-
ids 9.13 For some Fmoc-amino alcohols a slight variation
with catalytic amounts of pyridinium dichromate and pe-
riodic acid as principal oxidant proved superior.14 In a sin-
Due to this drawback, we have adopted a different strate-
gy based on racemization proof transformations of enan-
tiomerically pure common building blocks. In previous
studies, derivatives of allylglycine6 and vinylglycinol6,7
have been used as starting materials that were further
functionalized to aromatic amino acids by Suzuki or Heck
SYNTHESIS 2010, No. 2, pp 0293–0303
x
x
.
x
x
.2
0
0
9
Advanced online publication: 13.11.2009
DOI: 10.1055/s-0029-1217124; Art ID: T12409SS
© Georg Thieme Verlag Stuttgart · New York

294
M. Suhartono et al.
PAPER
OH
OH
Aryl
O
OH
OH
O
OMe
OMe
I
a
b
c
Boc
Boc
N
H
H2N
N
H
O
O
1
2
3
OH
e
f
d
Boc
N
Boc
Boc
N
N
O
O
O
4
7a–g
5
Aryl
OH
Aryl
g
Fmoc
Fmoc
OH
N
H
N
H
O
8a–g
9a–f
OMe
Aryl:
O
a
b
c
d
N
N
N
e
f
g
Scheme 1 Reagents and conditions: (a) 1. TMSCl, MeOH, 2. Boc2O, Et3N, quant. (2 steps); (b) LiBH4, THF, 93%; (c) Me2C(OMe)2, PTSA,
91%; (d) I2, Ph3P, DIPEA, 91%; (e) 1. Zn, I2, 2. Ar-X, NiCl2(PPh3)2, 80–95%; (f) 1. TFA, 2. Fmoc-OSu, 75–94%, (g) PDC, DMF, 79–92%,
>99% ee.
ZnI
O
N
a
OMe
10
6
HO
Boc
N
I
O
a
Fmoc
OH
Fmoc
OH
N
N
H
H
OMe
a
O
8g
12
N
Scheme 3 Oxidation of the anthracene amino alcohol 8g with PDC
in DMF
N
OMe
anthrone 12 (Scheme 3).7 The optimized reaction condi-
tions and yields of all steps are shown below (Table 1).
N
11
MeO
Boc
To rule out racemization in our new synthetic route, we
prepared ent-9a from D-glutamic acid (ent-1). The avail-
ability of the two enantiomers 9a and ent-9a allowed us to
verify >99% ee by chiral HPLC.
N
7h
O
Scheme 2 Homocoupling under Negishi conditions. Reagents and
conditions: (a) NiCl2(PPh3)2, DMF, 80 °C, 3 h.
Amino acids 9 are characterized by a C3-linker between
the glycine framework and the aromatic moiety. Applying
the methods shown in Scheme 1, we also succeeded in
synthesizing pyrene-substituted amino alcohol 19 with a
C2-linker from L-aspartic acid (Scheme 4). Compound 19
gle case, amino alcohol 8g, this final step failed due to
oxidative degradation of anthracene forming the hydroxy-
Synthesis 2010, No. 2, 293–303 © Thieme Stuttgart · New York

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Synthetic Aromatic Amino Acids
295
peptide synthesis. In our previous work, we have synthe-
sized amino acids of type 9 (C3-linker) from an allylglyci-
nol intermediate obtained in a diastereoselective Myers
alkylation.6 This approach is more laborious on a large
scale compared to the preparation of 5. Methionine, on the
other hand, can be easily transformed into enantiomerical-
ly pure vinylglycinol derivatives.6 Using either Suzuki6 or
Heck7 cross-coupling reactions, we have prepared C2-
linker amino acids such as 20 from this building block.
Apart from the linker length (C2 is also available from as-
partic acid, Scheme 4), how do the methods compare?
Compound 5 and the vinylglycinol derivative are both ac-
cessible in enantiomerically pure form in 30-gram batch-
es. The yields of the cross-coupling, deprotection, and
oxidation steps of both routes are almost equivalent. How-
ever, a major practical advantage of the new method is the
fast and simplified deprotection of intermediates 7 and 18
(step f in Schemes 1 and 4) reducing the time requirement
of the synthesis. The preparation and evaluation of pep-
tides prepared from building blocks 9 and 20 will be re-
ported elsewhere.
Table 1 Reaction Conditions and Yields
7–9
a
Yield (%) of 7
Yield (%) of 8
Yield (%) of 9
88a
84b
85a
95a
87a
86a
80a
91c
78c
88c
75c
85c
94d
85c
83e
80e
92e
70f
82f
79g
–
b
c
d
e
f
g
a (1) Zn, I2, DMF, 40 °C, 1 h; (2) NiCl2(PPh3)2, ArBr, 80 °C, 3 h.
b (1) Zn, I2, DMF, 40 °C, 1 h; (2) NiCl2(PPh3)2, 2-iodo-6-methoxy-
naphthalene, 80 °C, 3 h.
c (1) TFA, r.t., 1 h; (2) Fmoc-OSu, EtOAc–EtOH (2:1), r.t., ~2 h.
d (1) TFA, r.t., 1 h; (2) Fmoc-OSu, DIPEA, EtOAc–EtOH (2:1), r.t.,
~2 h.
e PDC, DMF, 40 °C, 8 h.
f PDC, H5IO6, DMF, 40 °C, 8 h.
g PDC, H5IO6, acetone, r.t., overnight.
NMR: Bruker DPX 250 (1H: 250 MHz; 13C: 62.9 MHz), Bruker AM
300 (1H: 300 MHz; 13C: 75.4 MHz) or Bruker Avance 400 (1H: 400
MHz; 13C: 100.6 MHz). FT-IR: Perkin-Elmer 1600 Series or Jasco
420. Elementary analysis: Heraeus CHN Rapid. Mass spectrometry:
Fisons VG Platform II (ESI); Fisons VG Tofspec (MALDI).
Melting points (uncorrected): Kofler hot plate microscope. Optical
rotation: Perkin-Elmer polarimeter 241.
has been prepared previously from vinylglycinol using the
Heck pathway. Its conversion into amino acid 20 is
known.7
In summary, we have developed an efficient synthesis of
Fmoc-protected aromatic a-amino acids from L- or D-
glutamic acid. The enantiopure building block 5 was con-
verted easily into the organozinc species 6 which under-
goes nickel-catalyzed Negishi cross coupling in high
yields (80–95%). Our synthesis comprises ten steps in to-
tal with combined yields up to 53%. The final building
blocks 9 are ready for further application in solid-phase
Dimethyl (2S)-2-[(tert-Butoxycarbonyl)amino]pentanedioate
(2)
To a 1000-mL round-bottom flask containing ice-cold MeOH (300
mL) was added TMSCl (108 mL, 850 mmol) and then L-glutamic
acid (1, 25.0 g, 170 mmol) was added in small portions. The mixture
OH
O
O
O
OH
a
OH
OMe
OMe
b
Boc
OH
Boc
N
H2N
N
H
H
O
c
13
14
15
OH
I
d
e
Boc
Boc
N
N
O
O
16
17
f
g
Boc
N
Fmoc
OH
Fmoc
OH
N
H
N
O
H
O
18
19
20
Scheme 4 Reagents and conditions: (a) (1) TMSCl, MeOH, (2) Boc2O, Et3N, 95% (2 steps); (b) LiBH4, THF, 88%; (c) Me2C(OMe)2, PTSA,
85%; (d) I2, Ph3P, DIPEA, 49%; (e) 1. Zn, I2, 2. 1-bromopyrene, NiCl2(PPh3)2, 64%; (f) 1. TFA, 2. Fmoc-OSu, 68%; (g) see ref. 7. Yields were
not optimized.
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296
M. Suhartono et al.
PAPER
was stirred at r.t. overnight. After quantitative conversion, the mix-
ture was cooled to 0 °C. Et3N (153 mL, 1.1 mol) and Boc2O (40.8
g, 187 mmol) were added slowly to the soln. The turbid mixture was
diluted with MeOH (100 mL) and stirred again at r.t. overnight. The
mixture was concentrated in vacuo, the residue was suspended in
Et2O (500 mL) and filtered through Celite. The filtrate was concen-
trated under reduced pressure and purified by column chromatogra-
phy (n-hexane–EtOAc, 2:1) to give 2 (46.8 g, quant.) as a colorless
oil; Rf = 0.4 (n-hexane–EtOAc, 1:1).
Anal. Calcd for C10H21NO4: C, 54.77; H, 9.65; N, 6.39. Found: C,
54.94; H, 9.84; N, 6.37.
tert-Butyl (4S)-4-(3-Hydroxypropyl)-2,2-dimethyloxazolidine-
3-carboxylate (4)
Diol 3 (29.0 g, 132 mmol) was dissolved in CH2Cl2 (300 mL). 2,2-
Dimethoxypropane (243 mL, 1.98 mol) and PTSA·H2O (2.51 g,
13.2 mmol) were added. The mixture was stirred at r.t. for exactly
90 min. Sat. NaHCO3 (150 mL) was added and the aqueous phase
was extracted with EtOAc (3 × 150 mL). The combined organic
phases were dried (MgSO4), concentrated in vacuo, and purified by
column chromatography (n-hexane–EtOAc, 10:1) to give 4 (31.3 g,
91%) as a colorless oil; Rf = 0.6 (n-hexane–EtOAc, 2:1).
[a]D20 –26.0 (c 1.0, MeOH).
IR (film): 3372 (m), 2978 (s), 1714 (s), 1518 (s), 1439 (s), 1367 (s),
1252 (s), 1168 (s), 1051 (m), 1028 (m), 881 (w), 857 (w), 780 (w),
586 cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 7.28 (d, J = 7.8 Hz, 1 H, NH,
D2O exch.), 3.99 (m, 1 H, CH), 3.62 (s, 3 H, CHCO2CH3), 3.58 (s,
3 H, CH2CO2CH3), 2.37 (m, 2 H, CH2CO2CH3), 1.99 (m, 1 H,
CHCHa), 1.77 (m, 1 H, CHCHb), 1.37 [s, 9 H, C(CH3)3].
[a]D20 +36.4 (c 0.5, MeOH).
IR (film): 3447 (s), 2979 (s), 2936 (s), 2871 (m), 1698 (s), 1478 (m),
1457 (m), 1390 (s), 1257 (m), 1207 (m), 1175 (s), 1148 (m), 1087
(s), 1030 (m), 946 (w), 845 (m), 806 (m), 769 (m), 662 (w), 560
cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 4.39 (t, J = 5.3 Hz, 1 H, OH,
D2O exch.), 3.88 (dd, J = 8.5 Hz, J = 5.5 Hz, 1 H, CHCHHO), 3.74
(m, 1 H, NCH), 3.68 (dd, J = 8.5 Hz, J = 1.25 Hz, 1 H, CHCHHO),
3.38 (dt, J = 6.3 Hz, J = 5.3 Hz, 2 H, CH2OH), 1.64 (m, 2 H, CH2),
1.47 (s, 3 H, CH3), 1.41 (s, 9 H, CH2, CH3), 1.39–1.32 (m, 5 H,
CH3).15
13C NMR (62.9 MHz, DMSO-d6): d = 173.6, 172.5, 155.4, 78.2,
52.5, 51.7, 51.3, 29.6, 28.1, 25.8.
Anal. Calcd for C12H21NO6: C, 52.35; H, 7.69; N, 5.09. Found: C,
52.33; H, 7.77; N, 5.24.
Dimethyl (2R)-2-[(tert-Butoxycarbonyl)amino]pentanedioate
(ent-2)
Compound ent-2 was synthesized by the same procedure. NMR and
IR spectra are identical with those of 2.
13C NMR (62.9 MHz, DMSO-d6): d = 151.0, 92.4, 78.8, 78.4, 66.4,
66.0, 60.5, 56.7, 29.9, 29.0, 27.9, 27.3, 26.5, 24.3, 22.9.15
Anal. Calcd for C13H25NO4: C, 60.21; H, 9.72; N, 5.40. Found: C,
60.00; H, 9.91; N, 5.43.
[a]D20 +26.0 (c 1.0, MeOH).
Anal. Calcd for C12H21NO6: C, 52.35; H, 7.69; N, 5.09. Found: C,
52.47; H, 7.87; N, 5.10.
tert-Butyl (4R)-4-(3-Hydroxypropyl)-2,2-dimethyloxazolidine-
3-carboxylate (ent-4)
tert-Butyl N-[(2S)-1,5-Dihydroxypentan-2-yl]carbamate (3)
In a flame-dried Schlenk vessel, THF (150 mL) was cooled in an ice
bath. LiBH4 (5.00 g, 230 mmol) was added under argon. Then 2
(12.5 g, 45.9 mmol) in THF (30 mL) was added dropwise to the
soln. The mixture was stirred at 0 °C for 1 h, then at r.t. overnight.
MeOH was added dropwise until gas evolution ceased. The turbid
soln was concentrated under reduced pressure. The residue was tak-
en up with H2O and extracted with EtOAc (3 × 120 mL). The com-
bined organic phases were dried (MgSO4) and concentrated in
vacuo. The residue was purified by column chromatography
(EtOAc–n-hexane, 10:1). The product was dried in vacuo to give 3
(9.34 g, 93%) as a colorless crystalline solid; mp 64–65 °C; Rf = 0.2
(EtOAc–n-hexane, 10:1).
Compound ent-4 was synthesized by the same procedure. NMR and
IR spectra are identical with those of 4.
[a]D20 –36.4 (c 0.5, MeOH).
Anal. Calcd for C13H25NO4: C, 60.21; H, 9.72; N, 5.40. Found: C,
60.30; H, 9.46; N, 5.57.
tert-Butyl (4S)-4-(3-Iodopropyl)-2,2-dimethyloxazolidine-3-
carboxylate (5)
Ph3P (27.6 g, 105 mmol) was dissolved in CH2Cl2 (250 mL) and I2
(26.7 g, 105 mmol) was added to the clear soln. After 5 min, DIPEA
(18.0 mL, 105 mmol) and alcohol 4 [24.8 g, 95.7 mmol, dissolved
in CH2Cl2 (50 mL)] were added. The mixture was stirred at r.t. for
2 h. Et2O (300 mL) was added and the precipitate was filtered
through Celite. The filtrate was washed successively with sat.
NaHCO3, Na2S2O5 soln, and H2O. The soln was dried (MgSO4) and
the solvent evaporated to give an oily brown residue that was puri-
fied by column chromatography (n-hexane–EtOAc, 10:1). The
product fractions were concentrated in vacuo and stored at –25 °C
to give 5 (32.2 g, 91%) as a colorless solid; mp 32 °C; Rf = 0.75 (n-
hexane–EtOAc, 3:1).
[a]D20 –15.1 (c 1.0, MeOH).
IR (KBr): 3347 (s), 2987 (m), 2941 (m), 2919 (s), 2867 (m), 1682
(s), 1534 (s), 1450 (m), 1389 (w), 1368 (m), 1300 (m), 1254 (m),
1171 (m), 1122 (w), 1075 (m), 1006 (m), 990 (m), 903 (w), 871 (w),
781 (w), 749 cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 6.43 (d, J = 8.3 Hz, 1 H, NH,
D2O exch.), 4.53 (t, J = 5.3 Hz, 1 H, CHCH2OH, D2O exch.), 4.34
(t, J = 5.3 Hz, 1 H, CH2CH2OH, D2O exch.), 3.39–3.15 (m, 5 H,
CH, CH2OH), 1.52 (m, 2 H, CH2), 1.37 [s, 9 H, C(CH3)3], 1.22 (m,
2 H, CH2).
[a]D20 +26.8 (c 1.0, MeOH).
IR (KBr): 2978 (m), 2936 (m), 2874 (w), 1693 (s), 1478 (m), 1455
(m), 1390 (s), 1313 (m), 1256 (s), 1208 (m), 1174 (s), 1096 (s), 977
(w), 860 (m), 846 (m), 806 (w), 769 (m), 558 cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 3.88 (dd, J = 8.5 Hz, J = 5.5
Hz, 1 H, CHCHHO), 3.76 (m, 1 H, NCH), 3.69 (d, J = 8.5 Hz, 1 H,
CHCHHO), 3.29 (m, 2 H, CH2I), 1.79–1.54 [m, 4 H, CH(CH2)2],
1.47 (s, 3 H, CH3), 1.42 (s, 9 H, CH3), 1.38 (s, 3 H, CH3).15
13C NMR (62.9 MHz, DMSO-d6): d = 155.3, 77.2, 63.6, 60.8, 52.1,
29.1, 28.2, 27.5.
Anal. Calcd for C10H21NO4: C, 54.77; H, 9.65; N, 6.39. Found: C,
54.96; H, 9.83; N, 6.36.
tert-Butyl N-[(2R)-1,5-Dihydroxypentan-2-yl]carbamate (ent-3)
Compound ent-3 was synthesized by the same procedure. NMR and
IR spectra are identical with those of 3.
13C NMR (62.9 MHz, DMSO-d6): d = 150.9, 92.6, 78.8, 78.6, 66.6,
66.2, 55.8, 34.1, 33.6, 29.7, 27.9, 27.3, 26.4, 24.2, 22.8, 8.6, 8.3.15
Anal. Calcd for C13H24INO3: C, 42.29; H, 6.55; N, 3.79. Found: C,
42.46; H, 6.64; N, 3.84.
[a]D20 +15.1 (c 1.0, MeOH).
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Synthetic Aromatic Amino Acids
297
tert-Butyl (4R)-4-(3-Iodopropyl)-2,2-dimethyloxazolidine-3-
carboxylate (ent-5)
Compound ent-5 was synthesized by the same procedure. NMR and
IR spectra are identical with those of 5.
tert-Butyl (4S)-4-[3-(6-Methoxynaphthalen-2-yl)propyl]-2,2-
dimethyloxazolidine-3-carboxylate (7b)
Following general procedure 1 using 2-iodo-6-methoxynaphthalene
(2.10 g) and column chromatography (n-hexane–EtOAc, 10:1) gave
7b as a colorless solid after recrystallization (MeCN); yield: 2.48 g
(84%); mp 95–97 °C; >99% ee [HPLC analysis (Chiral Whelk 01
RR column, n-hexane–i-PrOH, 2:1, 1.3 mL/min, 254 nm): tR = 3.15
(R), 4.13 min (S)]; Rf = 0.5 (n-hexane–EtOAc, 5:1).
[a]D20 –26.8 (c 1.0, MeOH).
Anal. Calcd for C13H24INO3: C, 42.29; H, 6.55; N, 3.79. Found: C,
42.36; H, 6.57; N, 3.91.
[a]D20 –19.8 (c 1.1, MeOH).
tert-Butyl 4-(3-Arylpropyl)-2,2-dimethyloxazolidine-3-carbox-
ylates 7a–g; General Procedure 1
IR (KBr): 2979 (m), 2942 (s), 2875 (m), 1703 (s), 1633 (w), 1605
(m), 1481 (w), 1456 (w), 1391 (s), 1371 (s), 1312 (w), 1257 (m),
1240 (m), 1160 (m), 1142 (m), 1096 (m), 1081 (m), 1026 (m), 889
(w), 856 (m), 815 (w), 769 (w), 677 cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 7.73 (d, J = 8.8 Hz, 2 H, Haryl),
7.60 (s, 1 H, Haryl), 7.32 (d, J = 8.3 Hz, 1 H, Haryl), 7.26 (d, J = 2.5
Hz, 1 H, Haryl), 7.11 (dd, J = 9 Hz, J = 2.5 Hz, 1 H, Haryl), 3.90–3.69
(m, 3 H, NCHCH2O), 3.85 (s, 3 H, OCH3), 2.71 (m, 2 H, ArCH2),
1.69–1.50 (m, 4 H, ArCH2CH2CH2), 1.44–1.37 (m, 10 H, CH3),
1.24 (s, 5 H, CH3).15
A 2-necked flask charged with Zn powder (0.72 g, 11.1 mmol) and
I2 (tip of a spatula) was flame dried for 10 min in vacuo. After flush-
ing with argon, anhyd DMF (7 mL) and alkyl iodide 5 (3.00 g, 8.13
mmol) were added and the mixture was stirred at 40 °C for 1 h (TLC
monitoring; the reaction was regarded as finished when only a base-
line spot was visible). After cooling to r.t., aryl halide (7.39 mmol)
and NiCl2(PPh3)2 (0.48 g, 0.74 mmol) were added under argon. The
mixture was stirred at 80 °C for 3 h. After cooling, brine (30 mL)
and EtOAc (40 mL) were added and the mixture was filtered
through Celite. The aqueous phase was extracted with EtOAc
(2 × 100 mL). The combined organic phases were dried (MgSO4)
and concentrated in vacuo. The residue was purified by column
chromatography.
13C NMR (100.6 MHz, DMSO-d6): d = 156.6, 150.9, 136.9, 132.6,
128.6, 128.5, 127.6, 126.5, 125.8, 118.3, 105.6, 92.5, 92.4, 78.9,
78.4, 66.4, 56.6, 55.0, 34.8, 32.7, 32.2, 27.8, 27.4, 26.5, 24.3, 22.9.15
Anal. Calcd for C24H33NO4: C, 72.15; H, 8.33; N, 3.51. Found: C,
71.91; H, 8.42; N, 3.70.
tert-Butyl (4S)-2,2-Dimethyl-4-[3-(pyren-1-yl)propyl]oxazoli-
dine-3-carboxylate (7a)
Following general procedure 1 using 1-bromopyrene (2.27 g) and
column chromatography (n-hexane–EtOAc, 25:1 then 10:1) gave
7a as a highly viscous oil; yield: 2.88 g (88%); >99% ee [HPLC
analysis (Chiral Whelk 01 RR column, n-hexane–i-PrOH, 10:1, 1.0
mL/min, 254 nm): tR = 6.90 (R), 10.85 min (S)]; Rf = 0.5 (n-hexane–
EtOAc, 5:1).
tert-Butyl (4R)-4-[3-(6-Methoxynaphthalen-2-yl)propyl]-2,2-
dimethyloxazolidine-3-carboxylate (ent-7b)
Compound ent-7b was synthesized by the same procedure. NMR
and IR spectra are identical with those of 7b.
[a]D20 +19.8 (c 1.1, MeOH).
Anal. Calcd for C24H33NO4: C, 72.15; H, 8.33; N, 3.51. Found: C,
72.24; H, 8.41; N, 3.62.
[a]D20 –10.5 (c 0.5, MeOH).
IR (film): 3040 (m), 2977 (m), 2934 (m), 2865 (m), 1694 (s), 1603
(w), 1509 (w), 1477 (m), 1457 (m), 1389 (s), 1364 (s), 1314 (m),
1257 (m), 1206 (m), 1174 (m), 1143 (m), 1097 (m), 1082 cm–1 (m).
tert-Butyl (4S)-2,2-Dimethyl-4-[3-(phenanthren-9-yl)propyl]ox-
azolidine-3-carboxylate (7c)
1H NMR (400 MHz, DMSO-d6): d = 8.32 (d, J = 9.2 Hz, 1 H, Haryl),
8.25 (m, 2 H, Haryl), 8.19 (m, 2 H, Haryl), 8.11 (m, 2 H, Haryl), 8.05
(m, 1 H, Haryl), 7.93 (m, 1 H, Haryl), 3.85 (m, 1 H, NCH), 3.69 (m, 2
H, OCH2), 3.33 (m, 2 H, ArCH2), 1.80–1.67 (m, 4 H,
ArCH2CH2CH2), 1.43–1.34 (m, 10 H, CH3), 1.06 (s, 5 H, CH3).15
Following general procedure 1 using 9-bromophenanthrene (2.64 g)
and column chromatography (n-hexane–EtOAc, 25:1 then 10:1)
gave 7c as a colorless solid after recrystallization (MeCN); yield:
2.64 g (85%); mp 102–103 °C; Rf = 0.65 (n-hexane–EtOAc, 3:1).
[a]D20 +17.2 (c 0.5, MeOH).
1H NMR (250 MHz, DMSO-d6, 90 °C): d = 8.36 (m, 9 H, Haryl),
3.92 (dd, J = 8.5 Hz, J = 6 Hz, 1 H, CHCHHO), 3.84 (m, 1 H,
NCH), 3.71 (dd, J = 8.5 Hz, J = 1.8 Hz, 1 H, CHCHHO), 3.37 (m,
2 H, ArCH2), 1.85–1.64 (m, 4 H, ArCH2CH2CH2), 1.46 (s, 3 H,
CH3), 1.41 (s, 3 H, CH3), 1.30 [s, 9 H, C(CH3)3].
13C NMR (75.4 MHz, DMSO-d6): d = 150.8, 136.5, 130.7, 130.3,
129.1, 127.9, 127.2, 127.0, 126.3, 125.9, 124.70, 124.67, 124.5,
124.1, 124.0, 123.2, 92.4, 78.9, 78.2, 66.4, 66.1, 56.6, 32.8, 32.3,
27.7, 27.5, 26.4, 24.2, 22.8.15
IR (KBr): 2984 (m), 2949 (m), 2876 (w), 1690 (s), 1625 (w), 1458
(w), 1388 (s), 1364 (s), 1250 (m), 1179 (m), 1084 (s), 1049 (w), 992
(w), 857 (w), 845 (w), 749 (m), 722 (m), 671 cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 8.87 (m, 1 H, Haryl), 8.78 (m, 1
H, Haryl), 8.13 (m, 1 H, Haryl), 7.90 (m, 1 H, Haryl), 7.72–7.58 (m, 5
H, Haryl), 3.91–3.70 (m, 3 H, NCHCH2O), 3.11 (m, 2 H, ArCH2),
1.87–1.60 (m, 4 H, ArCH2CH2CH2), 1.47–1.36 (m, 10 H, CH3),
1.16 (s, 5 H, CH3).15
13C NMR (75.4 MHz, DMSO-d6): d = 150.9, 136.0, 131.2, 130.5,
130.1, 129.0, 127.8, 126.6, 126.3, 126.0, 125.7, 124.2, 123.3, 122.5,
92.5, 78.4, 66.5, 56.6, 33.0, 32.3, 27.7, 26.4, 26.2, 22.9.15
Anal. Calcd for C29H33NO3: C, 78.52; H, 7.50; N, 3.16. Found: C,
78.68; H, 7.65; N, 3.17.
Anal. Calcd for C27H33NO3: C, 77.29; H, 7.93; N, 3.34. Found: C,
77.27; H, 8.04; N, 3.23.
tert-Butyl (4R)-2,2-Dimethyl-4-[3-(pyren-1-yl)propyl]oxazoli-
dine-3-carboxylate (ent-7a)
Compound ent-7a was synthesized by the same procedure. NMR
and IR spectra are identical with those of 7.
[a]D20 +10.5 (c 0.5, MeOH).
tert-Butyl (4S)-2,2-Dimethyl-4-[3-(4-phenoxyphenyl)propyl]ox-
azolidine-3-carboxylate (7d)
Following general procedure 1 using 4-bromophenyl phenyl ether
(1.84 g, 1.29 mL) and column chromatography (n-hexane–EtOAc,
10:1 then 3:1) gave 7d as a colorless oil; yield: 2.88 g (95%);
Rf = 0.65 (n-hexane–EtOAc, 3:1).
Anal. Calcd for C29H33NO3: C, 78.52; H, 7.50; N, 3.16. Found: C,
78.65; H, 7.53; N, 3.10.
[a]D20 +16.9 (c 1.2, MeOH).
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M. Suhartono et al.
PAPER
IR (film): 2979 (m), 2936 (m), 2865 (m), 1693 (s), 1591 (m), 1507
(m), 1490 (s), 1390 (s), 1238 (s), 1170 (m), 1097 (m), 871 (w), 848
(w), 750 (w), 692 cm–1 (w).
Anal. Calcd for C17H27N3O3: C, 63.53; H, 8.47; N, 13.07. Found: C,
63.28; H, 8.35; N, 13.12.
tert-Butyl (4R)-2,2-Dimethyl-4-[3-(pyrimidin-2-yl)propyl]ox-
azolidine-3-carboxylate (ent-7f)
Compound ent-7f was synthesized by the same procedure. NMR
and IR spectra are identical with those of 7f.
[a]D20 –31.5 (c 1.2, MeOH).
1H NMR (250 MHz, DMSO-d6): d = 7.36 (m, 2 H, Haryl), 7.20 (m, 2
H, Haryl), 7.10 (m, 1 H, Haryl), 6.94 (m, 4 H, Haryl), 3.87 (m, 1 H,
NCH), 3.70 (m, 2 H, CH2O), 2.57 (m, 2 H, ArCH2), 1.57 (m, 4 H,
ArCH2CH2CH2), 1.49–1.38 (m, 10 H, CH3), 1.33 (s, 5 H, CH3).15
13C NMR (62.9 MHz, DMSO-d6): d = 157.0, 154.3, 150.9, 137.1,
129.8, 129.6, 122.9, 118.6, 118.0, 92.5, 78.9, 78.4, 66.4, 66.0, 56.6,
34.1, 32.6, 27.9, 27.4, 26.5, 24.2, 22.9.15
Anal. Calcd for C17H27N3O3: C, 63.53; H, 8.47; N, 13.07. Found: C,
63.57; H, 8.61; N, 13.19.
Anal. Calcd for C25H33NO4: C, 72.96; H, 8.08; N, 3.40. Found: C,
72.87; H, 7.98; N, 3.19.
tert-Butyl (4S)-4-[3-(Anthracen-9-yl)propyl]-2,2-dimethylox-
azolidine-3-carboxylate (7g)
Following general procedure 1 using 9-bromoanthracene (1.90 g)
and column chromatography (n-hexane–EtOAc, 25:1 then 10:1)
gave 7g as a highly viscous oil; yield: 2.48 g (80%); Rf = 0.6 (n-hex-
ane–EtOAc, 5:1).
tert-Butyl (4R)-2,2-Dimethyl-4-[3-(4-phenoxyphenyl)propyl]ox-
azolidine-3-carboxylate (ent-7d)
Compound ent-7d was synthesized by the same procedure. NMR
and IR spectra are identical with those of 7d.
[a]D20 –16.9 (c 1.2, MeOH).
[a]D20 +129.0 (c 0.5, MeOH).
IR (film): 2977 (m), 2934 (m), 1696 (s), 1624 (w), 1458 (w), 1389
(s), 1364 (s), 1259 (m), 1174 (m), 1101 (m); 1078 (m), 880 (w), 843
(w), 768 (w), 731 (m), 633 (w), 602 cm–1 (w).
Anal. Calcd for C25H33NO4: C, 72.96; H, 8.08; N, 3.40. Found: C,
72.76; H, 8.28; N, 3.20.
tert-Butyl (4S)-2,2-Dimethyl-4-[3-(quinolin-3-yl)propyl]oxazo-
lidine-3-carboxylate (7e)
Following general procedure 1 using 3-bromoquinoline (1.54 g, 995
mL) and column chromatography (n-hexane–EtOAc, 3:1) gave 7e as
a colorless oil; yield: 2.38 g (87%); Rf = 0.6 (n-hexane–EtOAc,
1:1).
1H NMR (250 MHz, DMSO-d6): d = 8.47 (s, 1 H, Haryl), 8.31 (d,
J = 8.5 Hz, 2 H, Haryl), 8.07 (m, 2 H, Haryl), 7.57–7.47 (m, 4 H, Haryl),
3.90–3.62 (m, 5 H, NCHCH2O, ArCH2), 1.74–1.56 (m, 4 H,
ArCH2CH2CH2), 1.47–1.34 (m, 10 H, CH3), 1.16 (s, 5 H, CH3).15
13C NMR (100.6 MHz, DMSO-d6): d = 150.9, 134.5, 131.0, 129.0,
128.9, 125.5, 125.3, 124.8, 124.2, 92.5, 79.0, 78.3, 66.5, 56.6, 33.3,
32.9, 27.9, 27.6, 26.6, 26.4, 24.3, 22.9.15
[a]D20 +16.2 (c 0.6, MeOH).
IR (film): 2978 (s), 2935 (s), 2865 (m), 1686 (s), 1570 (w), 1496
(m), 1458 (m), 1388 (s), 1257 (s), 1206 (m), 1175 (m), 1101 (s),
1075 (s), 984 (w), 908 (w), 847 (m), 788 (m), 753 (m), 614 cm–1
(m).
Anal. Calcd for C27H33NO3: C, 77.29; H, 7.93; N, 3.34. Found: C,
77.42; H, 8.07; N, 3.29.
2-Methoxy-6-(2-methoxyquinolin-6-yl)quinoline (11)
Following general procedure 1 using 6-iodo-2-methoxyquinoline
(750 mg, 2.63 mmol), NiCl2(PPh3)2 (172 mg, 0.26 mmol), 5 (1.07
g, 2.89 mmol), Zn powder (258 mg, 3.95 mmol), and DMF (4 mL)
with column chromatography (n-hexane–EtOAc, 10:1) gave 11 as a
colorless solid after recrystallization (MeCN); yield: 370 mg (89%);
mp 218 °C; Rf = 0.55 (n-hexane–EtOAc, 3:1).
1H NMR (250 MHz, DMSO-d6): d = 8.80 (d, J = 2.3 Hz, 1 H, Haryl),
8.14 (d, J = 1.8 Hz, 1 H, Haryl), 7.98 (d, J = 8.5 Hz, 1 H, Haryl), 7.90
(d, J = 8 Hz, 1 H, Haryl), 7.69 (m, 1 H, Haryl), 7.57 (m, 1 H, Haryl),
3.91–3.72 (m, 3 H, NCHCH2O), 2.81 (m, 2 H, ArCH2), 1.75–1.52
(m, 4 H, ArCH2CH2CH2), 1.45–1.37 (m, 10 H, CH3), 1.20 (s, 5 H,
CH3).15
IR (KBr): 2988 (w), 2943 (w), 1624 (m), 1599 (s), 1471 (s), 1390
(s), 1326 (s), 1287 (m), 1257 (s), 1196 (w), 1117 (w), 1016 (m), 968
(w), 908 (w), 874 (m), 826 (m), 712 (w), 671 (w), 634 (w), 558
cm–1 (w).
13C NMR (62.9 MHz, DMSO-d6): d = 151.8, 150.9, 146.2, 134.8,
133.7, 128.5, 128.4, 127.6, 127.4, 126.4, 92.5, 78.9, 78.3, 66.3,
66.0, 56.5, 32.0, 27.8, 27.0, 26.5, 24.3, 22.9.15
UV (EtOH–H2O, 2:1): lmax (e) = 229 nm (39900).
1H NMR (300 MHz, DMSO-d6): d = 8.33 (d + d, J = 2.1 Hz, J = 8.7
Hz, 2 H + 2 H, H5aryl, H5¢aryl, H4aryl, H4¢aryl), 8.14 (dd, J = 8.7 Hz,
Anal. Calcd for C22H30N2O3: C, 71.32; H, 8.16; N, 7.56. Found: C,
71.06; H, 8.13; N, 7.29.
J = 2.1 Hz, 2 H, H7aryl, H7¢aryl), 7.90 (d, J = 8.7 Hz, 2 H, H8aryl
,
H8¢aryl), 7.08 (d, J = 8.7 Hz, 2 H, H3aryl, H3¢aryl), 4.02 (s, 6 H, CH3).
tert-Butyl (4S)-2,2-Dimethyl-4-[3-(pyrimidin-2-yl)propyl]ox-
azolidine-3-carboxylate (7f)
Following general procedure 1 using 2-bromopyrimidine (1.17 g)
and column chromatography (n-hexane–EtOAc, 3:1) gave 7f as a
colorless oil; yield: 2.05 g (86%); Rf = 0.3 (n-hexane–EtOAc, 1:1).
13C NMR (75.4 MHz, DMSO-d6): d = 162.0, 145.2, 139.4, 135.0,
128.5, 127.2, 125.3, 125.0, 113.3, 53.0.
MS (ESI): m/z (%) = 317.2 (100) [M + H]+.
Anal. Calcd for C20H16N2O2: C, 75.93; H, 5.10; N, 8.86. Found: C,
75.78; H, 5.15; N, 8.73.
[a]D20 +31.5 (c 1.2, MeOH).
IR (film): 2978 (s), 2936 (s), 2870 (m), 1695 (s), 1562 (s), 1478 (m),
1425 (s), 1390 (s), 1314 (m), 1257 (s), 1207 (m), 1175 (s), 1092 (s),
944 (w), 849 (m), 806 cm–1 (m).
1H NMR (250 MHz, DMSO-d6): d = 8.71 (d, J = 4.8 Hz, 2 H,
Hpym4/6), 7.32 (t, J = 4.8 Hz, 1 H, Hpym5), 3.91–3.68 (m, 3 H,
NCHCH2O), 2.87 (m, 2 H, ArCH2), 1.69 (m, 2 H, Ar(CH2)2CH2),
1.45–1.33 [m, 17 H, ArCH2CH2, NC(CH3)2, C(CH3)3].15
9H-Fluoren-9-ylmethyl N-(5-Aryl-1-hydroxypentan-2-yl)car-
bamates 8a–g; General Procedure 2
In a round bottom flask the Negishi coupling product 7 (1.0 equiv)
was treated with TFA (neat) and stirred at r.t. for 1 h. The mixture
was cooled to 0 °C and aq 2 M NaOH was added until the pH of the
soln became basic. The mixture was extracted with EtOAc (3 ×).
The combined organic phases were dried (MgSO4) and concentrat-
ed in vacuo. The residue was dissolved in EtOAc–EtOH (2:1) and
Fmoc-OSu (1.05 equiv) was added and the mixture was stirred at r.t.
for at least 2 h. The precipitate was filtered and washed with ice-
13C NMR (62.9 MHz, DMSO-d6): d = 170.0, 157.0, 151.0, 118.8,
92.5, 78.9, 78.4, 66.4, 56.5, 32.7, 32.1, 27.9, 26.5, 24.3, 22.9.15
UV (EtOH–H2O, 2:1): lmax (e) = 248 nm (3400).
Synthesis 2010, No. 2, 293–303 © Thieme Stuttgart · New York

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Synthetic Aromatic Amino Acids
299
cold EtOAc–EtOH. Recrystallization (MeCN) gave a colorless sol-
id.
(4 mL), Fmoc-OSu (954 mg, 2.83 mmol), and EtOAc–EtOH (2:1,
15 mL); yield: 1.19 g (88%); mp 182 °C; Rf = 0.25 (n-hexane–
EtOAc, 1:1).
9H-Fluoren-9-ylmethyl N-[(2S)-1-Hydroxy-5-(pyren-1-yl)pen-
tan-2-yl]carbamate (8a)
Following general procedure 2 using 7a (950 mg, 2.14 mmol), TFA
(4 mL), Fmoc-OSu (759 mg, 2.25 mmol), and EtOAc–EtOH (2:1,
10 mL); yield: 1.03 g (91%); mp 187 °C; Rf = 0.3 (n-hexane–
EtOAc, 1:1).
[a]D20 –2.4 (c 0.5, DMF).
IR (KBr): 3321 (m), 3063 (w), 2947 (w), 2865 (w), 1690 (s), 1543
(m), 1449 (m), 1276 (m), 1243 (m), 1147 (w), 1088 (w), 1043 (m),
999 (w), 888 (w), 759 (m), 740 (s), 671 (w), 619 cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 8.86 (d, J = 7.8 Hz, 1 H, Haryl),
8.78 (d, J = 8.3 Hz, 1 H, Haryl), 8.14 (d, J = 7.3 Hz, 1 H, Haryl), 7.91–
7.84 (m, 3 H, Haryl), 7.68–7.60 (m, 7 H, Haryl), 7.39–7.18 (m, 4 H,
Haryl), 7.08 (d, J = 8.5 Hz, 1 H, NH, D2O exch.), 4.64 (t, J = 5.3 Hz,
1 H, OH, D2O exch.), 4.35–4.16 (m, 3 H, CO2CH2CH), 3.55 (m, 1
H, NCH), 3.35 (m, 2 H, CH2OH), 3.09 (m, 2 H, ArCH2), 1.75 (m, 3
H, ArCH2CH2CHa), 1.49 (m, 1 H, ArCH2CH2CHb).
[a]D20 +30.5 (c 1.0, DMF).
IR (KBr): 3302 (m), 3039 (w), 2933 (m), 2857 (w), 1686 (s), 1547
(s), 1465 (m), 1449 (m), 1352 (w), 1299 (m), 1276 (m), 1244 (m),
1181 (w), 1134 (w), 1105 (m), 1085 (m), 1051 (m), 839 (s), 819 (w),
738 (s), 680 (w), 621 cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 8.34 (d, J = 9.3 Hz, 1 H, Haryl),
8.27–8.20 (m, 3 H, Haryl), 8.16–8.02 (m, 4 H, Haryl), 7.94 (d, J = 7.8
Hz, 1 H, Haryl), 7.84 (d, J = 7.5 Hz, 2 H, Haryl), 7.66 (d, J = 7.3 Hz,
2 H, Haryl), 7.38–7.16 (m, 4 H, Haryl), 7.08 (d, J = 8.8 Hz, 1 H, NH,
D2O exch.), 4.65 (t, J = 5.5 Hz, 1 H, OH, D2O exch.), 4.35–4.15 (m,
3 H, CO2CH2CH), 3.55 (m, 1 H, NCH), 3.48–3.22 (m, 4 H, CH2OH,
ArCH2), 1.75 (m, 3 H, ArCH2CH2CHa), 1.48 (m, 1 H,
ArCH2CH2CHb).
13C NMR (75.4 MHz, DMSO-d6): d = 155.4, 143.8, 140.6, 137.0,
130.8, 130.3, 129.1, 127.9, 127.3, 127.0, 126.8, 126.3, 125.9, 125.0,
124.8, 124.7, 124.6, 124.1, 124.0, 123.4, 119.9, 77.2, 63.7, 51.8,
46.7, 32.5, 31.0, 28.1.
13C NMR (75.4 MHz, DMSO-d6): d = 155.9, 143.8, 143.7, 140.5,
136.4, 131.3, 130.5, 130.0, 128.9, 127.7, 127.4, 126.8, 126.6, 126.2,
126.0, 125.6, 125.0, 124.2, 123.2, 122.5, 119.9, 65.0, 63.6, 52.5,
46.7, 32.5, 30.9, 26.4.
Anal. Calcd for C34H31NO3: C, 81.41; H, 6.23; N, 2.79. Found: C,
81.44; H, 6.23; N, 2.84.
9H-Fluoren-9-ylmethyl N-[(2S)-1-Hydroxy-5-(4-phenoxyphe-
nyl)pentan-2-yl]carbamate (8d)
Following general procedure 2 using 7d (1.75 g, 4.25 mmol), TFA
(5 mL), Fmoc-OSu (1.51 g, 4.46 mmol), and EtOAc–EtOH (2:1, 15
mL); yield: 1.57 g (75%); mp 94–96 °C; Rf = 0.4 (EtOAc–n-hexane,
1:1).
Anal. Calcd for C36H31NO3: C, 82.26; H, 5.94; N, 2.66. Found: C,
82.31; H, 5.98; N, 2.92.
[a]D20 –2.0 (c 0.5, DMF).
IR (KBr): 3335 (m), 3062 (w), 2938 (m), 2858 (m), 1688 (s), 1590
(m), 1535 (s), 1506 (m), 1488 (m), 1449 (m), 1321 (w), 1241 (s),
1164 (w), 1087 (m), 1042 (m), 978 (w), 870 (w), 830 (w), 737 (m),
691 cm–1 (m).
9H-Fluoren-9-ylmethyl N-[(2R)-1-Hydroxy-5-(pyren-1-yl)pen-
tan-2-yl]carbamate (ent-8a)
Compound ent-8a was synthesized by the same procedure. NMR
and IR spectra are identical with those of 8a.
1H NMR (250 MHz, DMSO-d6): d = 7.88 (d, J = 7.5 Hz, 2 H, Haryl),
7.69 (d, J = 7.5 Hz, 2 H, Haryl), 7.42–7.20 (m, 6 H, Haryl), 7.16–6.89
(m, 8 H, Haryl, NH, D2O exch.), 4.63 (t, J = 5.5 Hz, 1 H, OH, D2O
exch.), 4.36–4.17 (m, 3 H, CO2CH2CH), 3.46 (m, 1 H, NCH), 3.38–
3.20 (m, 2 H, CH2), 2.52 (m, 2 H, CH2), 1.54 (m, 3 H,
ArCH2CH2CHa), 1.30 (m, 1 H, ArCH2CH2CHb).
13C NMR (75.4 MHz, DMSO-d6): d = 156.9, 155.8, 154.3, 143.8,
140.6, 137.3, 129.8, 129.5, 127.4, 126.8, 125.0, 122.9, 119.9, 118.5,
118.0, 65.0, 63.4, 52.5, 46.7, 34.2, 30.4, 27.5.
[a]D20 –30.5 (c 1.0, DMF).
9H-Fluoren-9-ylmethyl N-[(2S)-1-Hydroxy-5-(6-methoxynaph-
thalen-2-yl)pentan-2-yl]carbamate (8b)
Following general procedure 2 using 7b (500 mg, 1.25 mmol), TFA
(1 mL), Fmoc-OSu (443 mg, 1.31 mmol), and EtOAc–EtOH (2:1,
10 mL); yield: 470 mg (78%); mp 149 °C; Rf = 0.4 (n-hexane–
EtOAc, 1:1).
[a]D20 +3.8 (c 0.5, DMF).
Anal. Calcd for C32H31NO4: C, 77.87; H, 6.33; N, 2.84; found: C,
77.61; H, 6.45; N, 2.92.
IR (KBr): 3320 (m), 3060 (w), 2939 (m), 1691 (s), 1634 (w), 1607
(m), 1540 (m), 1483 (m), 1450 (m), 1391 (w), 1264 (m), 1228 (m),
1160 (w), 1087 (w), 1033 (m), 852 (w), 810 (w), 759 (m), 740 (m),
670 (w), 621 cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 7.88 (d, J = 7.3 Hz, 2 H, Haryl),
7.73–7.68 (m, 4 H, Haryl), 7.58 (s, 1 H, Haryl), 7.42–7.35 (m, 2 H,
Haryl), 7.32–7.23 (m, 4 H, Haryl), 7.11 (dd, J = 8.8 Hz, J = 2.5 Hz, 1
H, Haryl), 7.04 (d, J = 8.8 Hz, 1 H, NH, D2O exch.), 4.61 (t, J = 5.5
Hz, 1 H, OH, D2O exch.), 4.37–4.17 (m, 3 H, CO2CH2CH), 3.85 (s,
3 H, OCH3), 3.48 (m, 1 H, NCH), 3.29 (m, 2 H, CH2OH), 2.69 (m,
2 H, ArCH2), 1.62 (m, 3 H, ArCH2CH2CHa), 1.34 (m, 1 H,
ArCH2CH2CHb).
9H-Fluoren-9-ylmethyl N-[(2S)-1-Hydroxy-5-(quinolin-3-
yl)pentan-2-yl]carbamate (8e)
Following general procedure 2 using 7e (1.13 g, 3.05 mmol), TFA
(5 mL), Fmoc-OSu (1.08 g, 3.20 mmol), and EtOAc–EtOH (2:1, 15
mL); yield: 1.17 g (85%); mp 127–128 °C; Rf = 0.2 (EtOAc–n-hex-
ane, 10:1).
[a]D20 –2.0 (c 0.5, DMF).
IR (KBr): 3420 (s), 3319 (s), 3062 (w), 2929 (m), 1690 (s), 1542
(m), 1450 (m), 1334 (w), 1244 (m), 1051 (m), 740 cm–1 (m).
13C NMR (75.4 MHz, DMSO-d6): d = 156.6, 155.8, 143.8, 140.6,
137.2, 132.5, 128.6, 128.5, 127.6, 127.4, 126.8, 126.5, 125.7, 125.1,
119.9, 118.2, 105.7, 65.0, 63.5, 55.0, 52.6, 46.7, 34.9, 30.5, 27.4.
1H NMR (250 MHz, DMSO-d6): d = 8.78 (d, J = 2 Hz, 1 H, Haryl),
8.10 (br s, 1 H, Haryl), 7.99 (d, J = 8.3 Hz, 1 H, Haryl), 7.88 (m, 3 H,
Haryl), 7.70 (m, 3 H, Haryl), 7.57 (m, 1 H, Haryl), 7.37 (m, 2 H, Haryl),
7.27 (m, 2 H, Haryl), 7.04 (d, J = 8.8 Hz, 1 H, NH, D2O exch.), 4.62
(t, J = 5.5 Hz, 1 H, OH, D2O exch.), 4.37–4.17 (m, 3 H,
CO2CH2CH), 3.49 (m, 1 H, NCH), 3.30 (m, 2 H, CH2OH), 2.78 (m,
2 H, ArCH2), 1.64 (m, 3 H, ArCH2CH2CHa), 1.35 (m, 1 H,
ArCH2CH2CHb).
Anal. Calcd for C31H31NO4: C, 77.31; H, 6.49; N, 2.91. Found: C,
77.16; H, 6.32; N, 2.93.
9H-Fluoren-9-ylmethyl N-[(2S)-1-Hydroxy-5-(phenanthren-9-
yl)pentan-2-yl]carbamate (8c)
Following general procedure 2 using 7c (1.13 g, 2.69 mmol), TFA
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13C NMR (75.4 MHz, DMSO-d6): d = 157.6, 151.8, 146.1, 143.8,
142.5, 140.6, 139.3, 137.3, 135.0, 133.6, 128.8, 128.5, 128.4, 127.6,
127.4, 127.1, 126.8, 126.3, 125.0, 121.2, 119.9, 109.5, 63.9, 52.1,
46.7, 32.1, 30.5, 27.1.
CH2OH), 3.33 (m, 2 H, ArCH2), 1.86 (m, 1 H, ArCH2CHa), 1.71 (m,
2 H, ArCH2CH2CHa), 1.58 (m, 1 H, ArCH2CH2CHb).
13C NMR (75.4 MHz, DMSO-d6): d = 155.9, 143.8, 143.7, 140.5,
134.8, 131.0, 128.9, 128.8, 127.4, 126.8, 125.5, 125.1, 124.9, 124.2,
119.9, 65.0, 63.8, 52.5, 46.7, 31.1, 27.6, 27.1.
Anal. Calcd for C29H28N2O3: C, 76.97; H, 6.24; N, 6.19. Found: C,
77.23; H, 6.30; N, 6.22.
Anal. Calcd for C34H31NO3: C, 81.41; H, 6.23; N, 2.79. Found: C,
81.13; H, 6.32; N, 2.87.
9H-Fluoren-9-ylmethyl N-[(2S)-1-Hydroxy-5-(pyrimidin-2-
yl)pentan-2-yl]carbamate (8f)
5-Aryl-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}pentano-
ic Acid; General Procedure 3
In a round-bottom flask 7f (1.80 g, 5.60 mmol) was treated with
TFA (5 mL) and stirred at r.t. for 1 h. The mixture was concentrated
and dried in vacuo, then the residue was dissolved in EtOAc–EtOH
(2:1, 15 mL). Fmoc-OSu (2.08 g, 6.16 mmol) and DIPEA (2.88 mL,
16.8 mmol) were added and the mixture was stirred at r.t. for at least
2 h. Brine (30 mL) was added and the mixture was extracted with
EtOAc (3 × 50 mL). The combined organic phases were dried
(MgSO4), concentrated under reduced pressure, and adsorbed on
silica gel. Purification by column chromatography (EtOAc–n-hex-
ane, 1:1, EtOAc, then EtOAc–MeOH, 9:1) and recrystallization
(MeCN) gave 8f (2.12 g, 94%) as a colorless solid; mp 73–75 °C;
Rf = 0.35 (EtOAc–MeOH, 9:1).
The Fmoc-amino alcohol 8 (1.0 equiv) was dissolved in DMF and
PDC was added. [In the case of 8e and 8d, H5IO6 was added.] The
mixture was stirred 40 °C for 8 h and then it was quenched with
brine (40 mL) and 6 M HCl (few drops). The soln was extracted
with EtOAc (3 × 50 mL). The combined organic phases were
washed with sat. Na2S2O5 soln, dried (MgSO4), and concentrated in
vacuo. The residue was purified by column chromatography
(EtOAc–n-hexane, 1:1, EtOAc, then EtOAc–MeOH, 9:1). Recrys-
tallization (CH2Cl2–n-hexane) gave a solid.
(2S)-2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-5-(pyren-
1-yl)pentanoic Acid (9a)
[a]D20 –6.7 (c 0.6, MeOH).
Following general procedure 3 using 8a (350 mg, 0.67 mmol), PDC
(1.25 g, 3.33 mmol), and DMF (5 mL) gave 9a as a light brown sol-
id; yield: 299 mg (83%); mp 115–116 °C; >99% ee [HPLC analysis
(Chiral DAICEL OJ-RH column, 0.1% TFA–MeCN, 42:58, 0.5
mL/min, 254 nm): tR = 35.28 (R), 38.51 min (S)]; Rf = 0.25
(EtOAc–MeOH, 9:1).
IR (KBr): 3317 (m), 3039 (w), 2947 (m), 1689 (s), 1561 (s), 1541
(s), 1450 (m), 1423 (m), 1245 (m), 1139 (w), 1085 (m), 1054 (m),
759 (m), 737 (m), 636 cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 8.70 (d, J = 4.8 Hz, 2 H, Haryl),
7.88 (d, J = 7.5 Hz, 2 H, Haryl), 7.70 (d, J = 7.3 Hz, 2 H, Haryl), 7.40
(t, J = 7.3 Hz, 2 H, Haryl), 7.34–7.26 (m, 3 H, Haryl), 7.04 (d, J = 8.5
Hz, 1 H, NH, D2O exch.), 4.61 (t, J = 5.5 Hz, 1 H, OH, D2O exch.),
4.35–4.17 (m, 3 H, CO2CH2CH), 3.46 (m, 1 H, NCH), 3.29 (m, 2 H,
CH2OH), 2.85 (m, 2 H, ArCH2), 1.67 (m, 3 H, ArCH2CH2CHa),
1.34 (m, 1 H, ArCH2CH2CHb).
[a]D20 +1.0 (c 1.0, DMF).
IR (KBr): 3424 (s), 3039 (w), 2936 (w), 1703 (s), 1655 (m), 1636
(m), 1562 (m), 1525 (m), 1458 (m), 1421 (m), 1349 (m), 1246 (m),
1055 (m), 844 (m), 740 cm–1 (m).
13C NMR (100.6 MHz, DMSO-d6): d = 170.2, 157.0, 155.9, 143.9,
140.6, 127.5, 126.9, 125.2, 120.0, 118.8, 65.1, 63.5, 52.7, 46.7,
38.6, 30.4, 24.6.
1H NMR (400 MHz, DMSO-d6): d = 12.59 (br s, 1 H, CO2H, D2O
exch.), 8.42–8.13 (m, 7 H, Haryl), 8.03 (m, 1 H, Haryl), 7.94 (d, J = 7.6
Hz, 1 H, Haryl), 7.86 (d, J = 7.2 Hz, 2 H, Haryl), 7.70 (m, 3 H, Haryl
,
NH, D2O exch.), 7.35 (m, 2 H, Haryl), 7.24 (m, 2 H, Haryl), 4.29–4.18
(m, 3 H, CO2CH2CH), 4.07 (m, 1 H, NCH), 3.35 (m, 2 H, ArCH2),
1.85 (m, 4 H, ArCH2CH2CH2).
Anal. Calcd for C24H25N3O3: C, 71.44; H, 6.25; N, 10.41. Found :
C, 71.23; H, 6.30; N, 10.34.
9H-Fluoren-9-ylmethyl N-[(2R)-1-Hydroxy-5-(pyrimidin-2-
yl)pentan-2-yl]carbamate (ent-8f)
Compound ent-8f was synthesized by the same procedure. NMR
and IR spectra are identical with those of 8f.
13C NMR (75.4 MHz, DMSO-d6): d = 173.8, 156.0, 143.7, 143.6,
140.6, 136.5, 130.8, 130.3, 129.1, 128.0, 127.4, 127.3, 127.0, 126.9,
126.3, 126.0, 125.1, 124.8, 124.6, 124.1, 124.0, 123.4, 119.9, 65.4,
53.7, 46.5, 32.1, 30.9, 28.0.
[a]D20 +6.7 (c 0.6, MeOH).
MS (ESI): m/z (%) = 404.1 (100) [M + H]+.
MS (MALDI): m/z (%) = 540.05 (100) [M + H]+, 495.87 (93) [M +
H – CO2]+, 317.29 (15) [M + H – Fmoc]+.
(2R)-2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-5-(pyren-
1-yl)pentanoic Acid (ent-9a)
Compound ent-9a was synthesized by the same procedure. NMR
and IR spectra are identical with those of 9a.
[a]D20 –1.0 (c 1.0, DMF).
9H-Fluoren-9-ylmethyl N-[(2S)-5-(Anthracen-9-yl)-1-hydroxy-
pentan-2-yl]carbamate (8g)
Following general procedure 2 using 7g (500 mg, 1.19 mmol), TFA
(2 mL), Fmoc-OSu (422 mg, 1.25 mmol), and EtOAc–EtOH (2:1,
10 mL) gave 8g as a colorless solid; yield: 510 mg (85%); mp 185–
186 °C; Rf = 0.4 (EtOAc–n-hexane, 1:1).
(2S)-2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-5-(6-
methoxynaphthalen-2-yl)pentanoic Acid (9b)
Following general procedure 3 using 8b (350 mg, 0.73 mmol), PDC
(1.64 g, 5.09 mmol), and DMF (5 mL) gave 9b as a light brown sol-
id; yield: 287 mg (80%); mp 101 °C; Rf = 0.3 (EtOAc–MeOH, 9:1).
[a]D20 –1.6 (c 0.3, DMF).
IR (KBr): 3424 (s), 3058 (m), 2947 (m), 1687 (s), 1544 (m), 1448
(m), 1384 (m), 1352 (m), 1301 (m), 1277 (m), 1240 (m), 1104 (w),
1085 (m), 1056 (m), 1021 (w), 878 (w), 836 (w), 789 (w), 758 (m),
738 (s), 560 cm–1 (w).
1H NMR (400 MHz, DMSO-d6): d = 8.47 (s, 1 H, Haryl), 8.31 (m, 2
H, Haryl), 8.07 (m, 2 H, Haryl), 7.82 (t, J = 7.2 Hz, 2 H, Haryl), 7.63 (d,
J = 7.2 Hz, 2 H, Haryl), 7.50 (m, 4 H, Haryl), 7.32 (t, J = 7.2 Hz, 2 H,
[a]D20 +2.0 (c 0.45, DMF).
IR (KBr): 3421 (s), 3063 (m), 2938 (m), 1688 (s), 1599 (s), 1525
(m), 1479 (m), 1449 (s), 1419 (s), 1350 (m), 1267 (s), 1159 (m),
1063 (m), 855 (w), 808 (w), 760 (m), 741 (m), 621 cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 12.52 (br s, 1 H, CO2H, D2O
exch.), 7.88 (d, J = 7.5 Hz, 2 H, Haryl), 7.75–7.65 (m, 5 H, Haryl, NH,
D2O exch.), 7.59 (s, 1 H, Haryl), 7.38 (m, 2 H, Haryl), 7.30–7.26 (m,
Haryl), 7.20 (t, J = 7.2 Hz, 1 H, Haryl), 7.11 (m, 2 H, Haryl, NH, D2O
exch.), 4.69 (t, J = 5.6 Hz, 1 H, OH, D2O exch.), 4.27 (m, 2 H,
CO2CH2CH), 4.16 (m, 1 H, CO2CH2CH), 3.67–3.49 (m, 3 H, NCH,
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Synthetic Aromatic Amino Acids
301
4 H, Haryl), 7.12 (dd, J = 9 Hz, J = 2.3 Hz, 1 H, Haryl), 4.30–4.18 (m,
3 H, CO2CH2CH), 4.00 (m, 1 H, NCH), 3.85 (s, 3 H, OCH3), 2.70
(m, 2 H, ArCH2), 1.71 (m, 4 H, ArCH2CH2CH2).
IR (KBr): 3422 (m), 3328 (m), 3063 (w), 2938 (m), 2862 (w), 1700
(s), 1534 (m), 1499 (m), 1450 (m), 1388 (w), 1233 (s), 1152 (m),
1134 (m), 1084 (m), 1054 (m), 912 (w), 758 (s), 740 cm–1 (s).
13C NMR (75.4 MHz, DMSO-d6): d = 173.7, 156.6, 156.0, 143.7,
140.6, 136.8, 132.6, 128.6, 128.4, 127.6, 127.4, 126.9, 126.5, 125.8,
125.1, 119.9, 118.3, 105.7, 65.4, 55.0, 53.5, 46.5, 34.4, 30.4, 27.2.
1H NMR (250 MHz, DMSO-d6): d = 12.35 (br s, 1 H, CO2H, D2O
exch.), 8.79 (d, J = 2.3 Hz, 1 H, Haryl), 8.12 (d, J = 1.3 Hz, 1 H,
Haryl), 7.99 (d, J = 8.3 Hz, 1 H, Haryl), 7.89 (m, 3 H, Haryl), 7.73–7.55
(m, 5 H, Haryl, NH, D2O exch.), 7.39 (m, 2 H, Haryl), 7.29 (m, 2 H,
Haryl), 4.30–4.18 (m, 3 H, CO2CH2CH), 4.03 (m, 1 H, NCH), 2.80
(m, 2 H, ArCH2), 1.76–1.60 (m, 4 H, ArCH2CH2CH2).
13C NMR (75.4 MHz, DMSO-d6): d = 173.7, 156.0, 151.8, 146.2,
143.7, 140.6, 134.6, 133.8, 128.5, 127.6, 127.5, 127.4, 126.9, 126.4,
125.13, 125.10, 119.9, 65.5, 53.5, 46.6, 31.6, 30.2, 26.9.
MS (ESI): m/z (%) = 272.0 (100) [M – H – Fmoc]–, 298.0 (33.62)
[M – H – fluorenylmethanol]–, 494.3 (72.69) [M – H]–, 530.3
(22.73) [M + 35Cl]–, 532.3 (11.52) [M + 37Cl]–.
(2S)-2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-5-
(phenanthren-9-yl)pentanoic Acid (9c)
Following general procedure 3 using 8c (180 mg, 0.36 mmol), PDC
(1.35 g, 3.60 mmol), and DMF (4 mL) gave 9c as a light brown sol-
id; yield: 171 mg (92%); mp 119–120 °C; Rf = 0.25 (EtOAc–
MeOH, 9:1).
MS (ESI): m/z (%) = 687.6 (9.99) [M – H + Fmoc]–, 465.1 (57.69)
[M – H]–, 343.1 (57.40) [M – 2 H + Fmoc]2–, 269.0 (72.31) [M –
H – fluorenylmethanol]–, 243.0 (100.0) [M – H – Fmoc]–.
[a]D20 –3.0 (c 0.4, DMF).
(2S)-2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-5-(pyrimi-
din-2-yl)pentanoic Acid (9f)
IR (KBr): 3422 (s), 3066 (m), 2950 (m), 2867 (m), 1700 (s), 1638
(m), 1542 (m), 1527 (m), 1449 (m), 1423 (m), 1343 (m), 1244 (m),
1081 (m), 1053 (m), 947 (w), 892 (w), 741 cm–1 (s).
1H NMR (250 MHz, DMSO-d6): d = 8.85 (m, 1 H, Haryl), 8.78 (m, 1
H, Haryl), 8.13 (d, J = 8.0 Hz, 1 H, Haryl), 7.86 (m, 3 H, Haryl), 7.68–
7.56 (m, 7 H, Haryl), 7.36 (m, 2 H, Haryl), 7.25 (m, 2 H, Haryl), 7.03
(br s, 1 H, NH), 4.29–4.16 (m, 3 H, CO2CH2CH), 3.87 (m, 1 H,
NCH), 3.07 (m, 2 H, ArCH2), 1.92–1.63 (m, 4 H, ArCH2CH2CH2).
The CO2H signal was not observed.
13C NMR (75.4 MHz, DMSO-d6): d = 155.5, 143.8, 140.5, 136.4,
131.3, 130.6, 130.0, 128.9, 127.7, 127.4, 126.9, 126.6, 126.2, 126.0,
125.5, 125.1, 125.0, 124.3, 123.3, 122.5, 119.9, 65.2, 54.8, 46.6,
32.4, 32.1, 26.2. The CO2H signal was not observed.
The Fmoc-amino alcohol 8f (620 mg, 1.54 mmol) was dissolved in
acetone (10 mL). PDC (56 mg, 0.15 mmol) and H5IO6 (1.65 g, 7.70
mmol) were added to the clear soln. The mixture was stirred over-
night at r.t. and then it was treated with brine (20 mL) and 6 M HCl
(few drops). The soln was extracted with EtOAc (3 × 50 mL). The
combined organic phases were washed with sat. Na2S2O5 soln, dried
(MgSO4), and concentrated in vacuo. The residue was purified by
column chromatography (EtOAc–n-hexane, 1:1, EtOAc, then
EtOAc–MeOH, 9:1). Recrystallization (MeCN–H2O) gave 9f (504
mg, 79%) as a yellow solid; mp 61–63 °C; Rf = 0.2 (EtOAc–MeOH,
2:1).
[a]D20 –1.9 (c 0.4, MeOH).
IR (KBr): 3339 (s), 3066 (m), 2943 (m), 1698 (s), 1543 (s), 1449
(m), 1332 (m), 1267 (s), 1199 (s), 1140 (m), 1056 (m), 834 (w), 803
(w), 761 (m), 740 (m), 648 cm–1 (w).
1H NMR (400 MHz, DMSO-d6): d = 12.53 (br s, 1 H, CO2H, D2O
exch.), 8.72 (d, J = 4.8 Hz, 2 H, Haryl), 7.89 (d, J = 7.7 Hz, 2 H,
MS (MALDI): m/z (%) = 554.91 (100) [M + K]+.
(2S)-2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-5-(4-phe-
noxyphenyl)pentanoic Acid (9d)
Following general procedure 3 using 8d (200 mg, 0.41 mmol), PDC
(150 mg, 0.41 mmol), H5IO6 (547 mg, 2.43 mmol), and DMF (3
mL) gave 9d as a colorless solid; yield: 144 mg (70%); mp 59–60
°C; Rf = 0.3 (EtOAc–MeOH, 9:1).
Haryl), 7.72 (d, J = 7.2 Hz, 2 H, Haryl), 7.67 (d, J = 8 Hz, 1 H, NH,
D2O exch.), 7.41 (t, J = 7.2 Hz, 2 H, Haryl), 7.34–7.29 (m, 3 H, Haryl),
4.27 (m, 2 H, CO2CH2CH), 4.22 (m, 1 H, CO2CH2CH), 3.98 (m, 1
H, NCH), 2.87 (m,
2 H, ArCH2), 1.83–1.73 (m, 3 H,
[a]D20 –1.5 (c 0.4, DMF).
ArCH2CH2CHa), 1.67 (m, 1 H, ArCH2CH2CHb).
13C NMR (75.4 MHz, DMSO-d6): d = 173.7, 169.8, 157.0, 156.0,
143.6, 140.6, 127.5, 126.9, 125.1, 119.9, 118.8, 65.5, 53.5, 46.5,
38.0, 30.2, 24.4.
IR (KBr): 3402 (m), 3036 (m), 2924 (s), 2854 (m), 1719 (s), 1590
(m), 1507 (s), 1489 (s), 1450 (m), 1417 (w), 1340 (w), 1238 (s),
1166 (w), 1106 (w), 1057 (w), 870 (w), 741 (m), 692 (w), 620
cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 12.55 (br s, 1 H, CO2H, D2O
exch.), 7.89 (d, J = 7.3 Hz, 2 H, Haryl), 7.74–7.65 (m, 3 H, Haryl, NH,
D2O exch.), 7.44–7.27 (m, 6 H, Haryl), 7.20 (d, J = 8.5 Hz, 2 H,
MS (ESI): m/z (%) = 418.2 (100) [M + H]+.
(2R)-2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-5-(pyrim-
idin-2-yl)pentanoic Acid (ent-9f)
[a]D20 +1.9 (c 0.4, MeOH).
Haryl), 7.11 (t, J = 7.3 Hz, 1 H, Haryl), 6.95 (m, 4 H, Haryl), 4.30–4.19
(m, 3 H, CO2CH2CH), 3.97 (m, 1 H, NCH), 2.56 (m, 2 H, ArCH2),
1.76–1.56 (m, 4 H, ArCH2CH2CH2).
13C NMR (75.4 MHz, DMSO-d6): d = 173.7, 156.9, 156.0, 154.4,
143.7, 140.6, 136.9, 129.8, 129.6, 127.5, 126.9, 125.1, 123.0, 120.0,
118.6, 118.0, 65.4, 53.5, 46.5, 33.7, 30.3, 27.4.
(2S)-2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-5-(9-hy-
droxy-10-oxo-9,10-dihydroanthracen-9-yl)pentanoic Acid (12)
Following general procedure 3 using 8g (100 mg, 0.20 mmol), PDC
(750 mg, 2.00 mmol), and DMF (1.5 mL) gave 12 as a colorless sol-
id; yield: 40 mg (37%); mp 104–106 °C; Rf = 0.5 (EtOAc–MeOH;
2:1).
Anal. Calcd for C32H29NO5: C, 75.72; H, 5.76; N, 2.76. Found: C,
75.59; H, 5.93; N, 2.74.
[a]D20 –8.9 (c 0.2, MeOH).
(2S)-2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-5-(quino-
lin-3-yl)pentanoic Acid (9e)
Following general procedure 3 using 8e (500 mg, 1.10 mmol), PDC
(420 mg, 1.10 mmol), H5IO6 (1.00 g, 4.40 mmol), and DMF (10
mL) gave 9e as a colorless solid; yield: 424 mg (82%); mp 103–105
°C; Rf = 0.3 (EtOAc–MeOH, 2:1).
IR (KBr): 3407 (s), 3066 (m), 2938 (m), 1705 (s), 1656 (s), 1600 (s),
1525 (m), 1450 (m), 1420 (m), 1320 (s), 1260 (m), 1215 (m), 1174
(m), 1074 (m), 932 (m), 818 (w), 760 (m), 741 (m), 695 (m), 622
cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 12.40 (br s, 1 H, CO2H, D2O
exch.), 8.06 (d, J = 7.5 Hz, 2 H, Haryl), 7.91 (m, 4 H, Haryl), 7.70 (m,
4 H, Haryl), 7.51–7.28 (m, 7 H, Haryl, NH, D2O exch.), 6.24 (br s, 1
[a]D20 –3.7 (c 0.4, DMF).
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M. Suhartono et al.
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H, OH, D2O exch.), 4.21–4.10 (m, 3 H, CO2CH2CH), 3.65 (m, 1 H,
NCH), 1.88 (m, 2 H, anthrone-CH2), 1.35 (m, 2 H, ArCH2CH2CH2),
0.73 (m, 2 H, ArCH2CH2).
13C NMR (75.4 MHz, DMSO-d6): d = 182.9, 173.4, 155.8, 148.4,
143.6, 140.5, 133.4. 130.0, 127.4, 126.9, 126.5, 126.4, 125.6, 125.1,
119.9, 71.1, 65.5, 53.2, 47.9, 46.5, 30.3, 20.2.
tert-Butyl (4S)-4-(2-Iodoethyl)-2,2-dimethyloxazolidine-3-car-
boxylate (17)
The synthetic procedure was analogous to that for 5; mp 35 °C;
Rf = 0.75 (n-hexane–EtOAc, 3:1).
[a]D20 +23.5 (c 1.5, MeOH).
IR (KBr): 2979 (s), 2936 (m), 2873 (m), 1696 (s), 1477 (m), 1457
(m), 1389 (s), 1365 (s), 1290 (m), 1257 (s), 1173 (s), 1084 (m), 1052
(m), 948 (w), 917 (w), 850 (m), 806 (w), 768 (m), 669 cm–1 (w).
MS (ESI): m/z (%) = 546.3 (100) [M – H]–, 324.0 (69.3) [M – H –
Fmoc]–, 350.0 (83.9) [M – H – fluorenylmethanol]–.
1H NMR (250 MHz, DMSO-d6): d = 3.87–3.79 (m, 3 H, NCH,
CH2), 3.30–3.09 (m, 2 H, CH2), 2.16–1.89 (m, 2 H, CH2CH2I),
1.46–1.21 (m, 15 H, CH3).15
13C NMR (62.9 MHz, MeOD-d4): d = 158.1, 101.1, 80.1, 74.1, 70.2,
68.5, 67.9, 67.3, 66.6, 65.3, 64.7, 63.3, 61.1, 56.2, 55.0, 54.4, 53.0,
37.0, 34.4, 33.4, 30.8, 28.8, 27.8, 27.3, 26.4, 26.0, 24.3, 24.1, 24.0,
23.7, 2.0, 0.2, –0.6.15
Dimethyl (2S)-2-[(tert-Butoxycarbonyl)amino]butanedioate
(14)
The synthetic procedure was analogous to that for 2; mp 56 °C;
Rf = 0.4 (n-hexane–EtOAc 1:1).
[a]D20 –17.9 (c 1.4, EtOH).
IR (KBr): 3408 (m), 2982 (m), 1740 (s), 1706 (s), 1508 (s), 1441
(m), 1378 (s), 1349 (s), 1296 (m), 1218 (s), 1160 (s), 1072 (w), 1032
(m), 998 (w), 869 (w), 844 (w), 782 (w), 685 (w), 592 cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 7.30 (d, J = 8.3 Hz, 1 H, NH,
D2O exch.), 4.37 (m, 1 H, NCH), 3.62 (s, 3 H, CHCO2CH3), 3.60 (s,
3 H, CH2CO2CH3), 2.66 (m, 2 H, CH2), 1.37 [s, 9 H, C(CH3)3].
Anal. Calcd for C12H22INO3: C, 40.58; H, 6.24; N, 3.94. Found: C,
40.53; H, 6.23; N, 4.11.
tert-Butyl (4S)-2,2-Dimethyl-4-[2-(pyren-1-yl)ethyl]oxazoli-
dine-3-carboxylate (18)
The synthetic procedure was analogous to that for 7a; Rf = 0.5 (n-
hexane–EtOAc 5:1).
[a]D20 +60.6 (c 1.0, MeOH).
13C NMR (75.4 MHz, DMSO-d6): d = 171.4, 170.3, 155.0, 78.4,
51.9, 51.5, 49.9, 35.6, 28.0.
Anal. Calcd for C11H19NO6: C, 50.57; H, 7.33; N, 5.36. Found: C,
50.58; H, 7.33; N, 5.40.
IR (KBr): 3340 (m), 2976 (m), 2934 (m), 2870 (m), 1693 (s), 1603
(w), 1543 (w), 1509 (w), 1477 (w), 1458 (w), 1387 (s), 1364 (s),
1247 (m), 1206 (m), 1173 (m), 1144 (m), 1095 (m), 1070 (m), 843
(s), 768 (m), 720 (m), 680 (w), 619 cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 8.34–7.94 (m, 9 H, Haryl),
4.10–3.86 (m, 3 H, CHCH2O, CHCH2O), 3.45–3.20 (m, 2 H,
ArCH2CH2), 1.98 (m, 2 H, NCHCH2CH2), 1.50–1.40 (m, 9 H, CH3),
1.18 (s, 6 H, CH3).15
13C NMR (75.4 MHz, DMSO-d6): d = 150.9, 135.9, 130.7, 130.2,
129.2 127.8, 127.3, 127.1, 126.4, 126.0, 124.9, 124.7, 124.2, 124.0,
123.0, 92.6, 79.0, 78.4, 66.1, 59.6, 56.8, 56.4, 35.1, 34.4, 29.1, 27.8,
27.3, 26.6, 24.3, 22.8, 20.6, 13.9.15
tert-Butyl N-[(2S)-1,4-Dihydroxybutan-2-yl]carbamate (15)
The synthetic procedure was analogous to that for 3; mp 45 °C;
Rf = 0.2 (EtOAc–n-hexane 10:1).
[a]D25 –31.0 (c 1.0, MeOH).
IR (KBr): 3376 (m), 2970 (m), 1693 (s), 1518 (s), 1391 (m), 1366
(s), 1296 (m), 1247 (s), 1172 (m), 1049 (s), 972 (m), 877 (m), 844
(w), 783 (w), 587 cm–1 (m).
1H NMR (250 MHz, DMSO-d6): d = 6.45 (d, J = 8.3 Hz, 1 H, NH,
D2O exch.), 4.55 (t, J = 5.5 Hz, 1 H, CHCH2OH, D2O exch.), 4.34
(t, J = 5.3 Hz, 1 H, CH2CH2OH, D2O exch.), 3.46–3.19 (m, 5 H,
CH, CH2OH), 1.64 (m, 1 H, NCHCHa), 1.45 (m, 1 H, NCHCHb),
1.37 [s, 9 H, C(CH3)3].
Anal. Calcd for C28H31NO3: C, 78.29; H, 7.27; N, 3.26. Found: C,
78.08; H, 7.31; N, 3.52.
13C NMR (62.9 MHz, DMSO-d6): d = 155.3, 77.3, 63.4, 57.9, 49.5,
9H-Fluoren-9-ylmethyl N-[(2S)-1-Hydroxy-4-(pyren-1-yl)bu-
tan-2-yl]carbamate (19)
The synthetic procedure was analogous to that for 8a; mp 160 °C;
34.3, 28.2.
Anal. Calcd for C9H19NO4: C, 52.67; H, 9.33; N, 6.82. Found: C,
52.84; H, 9.12; N, 6.90.
Rf = 0.3 (n-hexane–EtOAc, 1:1).
[a]D20 +30.1 (c 1.0, DMF).
tert-Butyl (4S)-4-(2-Hydroxyethyl)-2,2-dimethyloxazolidine-3-
carboxylate (16)
The synthetic procedure was analogous to that for 4; mp 44–47 °C;
Rf = 0.6 (n-hexane–EtOAc 2:1).
IR (KBr): 3464 (m), 3304 (s), 3037 (m), 2947 (m), 2870 (m), 1685
(s), 1603 (w), 1544 (s), 1444 (m), 1293 (m), 1268 (m), 1251 (m),
1104 (m), 1084 (m), 1056 (m), 1030 (m), 841 (s), 756 (m), 736 (s),
680 (w), 561 cm–1 (w).
[a]D20 +8.6 (c 1.0, MeOH).
1H NMR (400 MHz, DMSO-d6): d = 8.36 (d, J = 9.6 Hz, 1 H, Haryl),
8.27 (m, 2 H, Haryl), 8.19 (m, 2 H, Haryl), 8.12 (m, 2 H, Haryl), 8.95 (t,
J = 7.6 Hz, 1 H), 7.95–7.89 (m, 3 H, Haryl), 7.77 (t, J = 6.8 Hz, 2 H,
Haryl), 7.43–7.31 (m, 5 H, Haryl, NH, D2O exch.), 4.70 (t, J = 5.6 Hz,
1 H, OH, D2O exch.), 4.42 (m, 1 H, CO2CH2CH), 4.30 (m, 2 H,
CO2CH2CH), 3.62 (m, 1 H, NCH), 3.47–3.35 (m, 3 H, CH2CH2-ar-
yl, CHaHbOH), 3.24 (m, 1 H, CHaHbOH), 2.03 (m, 1 H, ArCH2CHa),
1.86 (m, 1 H, ArCH2CHb).
13C NMR (75.4 MHz, DMSO-d6): d = 156.0, 143.9, 143.8, 140.6,
136.7, 130.8, 130.3, 129.1, 128.8, 127.9, 127.5, 127.3, 127.0, 126.9,
126.3, 125.9, 125.1, 124.8, 124.7, 124.6, 124.1, 123.4, 121.2, 120.0,
65.1, 63.4, 52.7, 46.8, 33.1, 29.2.
IR (KBr): 3255 (m), 2979 (s), 2938 (s), 2881 (s), 1694 (s), 1482 (m),
1393 (s), 1311 (m), 1248 (m), 1220 (s), 1174 (s), 1084 (s), 1036 (m),
980 (m), 942 (w), 884 (m), 849 (w), 812 (w), 770 (m), 700 (w), 656
(w), 570 cm–1 (w).
1H NMR (250 MHz, DMSO-d6): d = 6.45 (t, J = 5.3 Hz, 1 H, OH,
D2O exch.), 3.87–3.54 (m, 3 H, CHCH2O, CHCH2O), 3.43 (m, 2 H,
CH2CH2OH), 1.77 (m, 1 H, NCHCHaHb), 1.59 (m, 1 H, NCH-
CHaHb), 1.46–1.38 (m, 14 H, CH3), 1.22 (m, 1 H, CH3).15
13C NMR (75.4 MHz, DMSO-d6): d = 154.7, 151.0, 127.9, 126.5,
126.1, 100.4, 99.2, 92.2, 78.9, 78.5, 77.6, 66.7, 66.4, 63.7, 61.3,
58.2, 57.7, 55.0, 49.3, 47.6, 39.4, 36.4, 35.5, 34.9, 28.1, 27.9, 27.3,
26.5, 24.6, 24.5, 24.3, 24.0, 22.9.15
Anal. Calcd for C35H29NO3: C, 82.17; H, 5.71; N, 2.74. Found: C,
82.92; H, 5.71; N, 3.00.
Anal. Calcd for C12H23NO4: C, 58.75; H, 9.45; N, 5.71. Found: C,
58.76; H, 9.34; N, 5.70.
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PAPER
Synthetic Aromatic Amino Acids
303
(5) Biotechnological synthesis of amino acids: Leuchtenberger,
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Acknowledgment
Financial support by the Deutsche Forschungsgemeinschaft (SFB
579 ‘RNA-Ligand Interactions’) is gratefully acknowledged. M.S.
would like to thank the Dr. Hilmer Foundation for a predoctoral fel-
lowship.
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(15) Due to the observed dynamic effects for the oxazolidine
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Synthesis 2010, No. 2, 293–303 © Thieme Stuttgart · New York