Synthesis of phenylalanine analogs

Article abstract of DOI:10.1002/jccs.200500150

A straight forward synthesis of phenylalanine analogs is described. Cerium ammonium nitrate (CAN) mediated addition of azide to cinnamicester, followed by reaction with sodium acetate aff orded the α-azidocinnamate in moderate yield. Hydrogenation of α-azidocinnamate, followed by BOC, CBZ or Fmoc protection gave phenylalanine analogs. A new approach for synthesizing racemic p-boronophenylalanine analog was also explored.

Full text of DOI:10.1002/jccs.200500150

Journal of the Chinese Chemical Society, 2005, 52, 1061-1067
1061
Note
Synthesis of Phenylalanine Analogs
Meng-Yang Changa* (
), Chun-Yu Lina (
) and Pei-Pei Sunb (
)
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan, R.O.C.
bCenter of General Studies, National Kaohsiung Marine University, Kaohsiung 811, Taiwan, R.O.C.
A straightforward synthesis of phenylalanine analogs is described. Cerium ammonium nitrate (CAN) me-
diated addition of azide to cinnamic ester, followed by reaction with sodium acetate afforded the a-azidocin-
namate in moderate yield. Hydrogenation of a-azidocinnamate, followed by BOC, CBZ or Fmoc protection
gave phenylalanine analogs. A new approach for synthesizing racemic p-boronophenylalanine analog was
also explored.
Keywords: Phenylalanine; Cerium ammonium nitrate; p-Boronophenylalanine; Hydrogenation; Pro-
tection.
INTRODUCTION
for synthesizing peptides or proteins with biological activi-
ties in high-throughput combinatorial chemistry.
Among the proteinogenic a-amino acids (AAs), phen-
CAN (cerium ammonium nitrate) was invented by
Smith et al. in 1936 and explored extensively in organic reac-
tions in industry and the academic fields.6 Representative ex-
amples include oxidation,7 oxidative addition,8 photooxida-
tion,9 nitration,10 deprotection,11 etc. Many research groups
successfully developed useful transformations by application
of this reagent. For example, Chavan8h developed a CAN-
mediated azidoalkoxylation of enol ethers and olefins. Hwu12
provided a practical way to the synthesis of a,b-unsaturated
nitroalkenes involving the use of CAN. In this paper, we wish
to report on the transformation of a,b-unsaturated esters into
phenylalanine analogs 1, associated with the use of CAN.
ylalanine (Phe, P) plays an important structural role in sev-
eral bioactive peptides. Replacement of phenylalanine with
constrained analogs is known to generate more effective ther-
apeutics.1-3 The pharmacological properties of a peptide with
phenylalanine motif are a function of its conformation, which
inturn is dictated by the constituent AAs. In this respect, un-
usual phenylalanine analogs are useful for carrying out more
systematic studies (e.g., QSAR).4 These well-defined struc-
tures are responsible for interesting biological properties.
To appreciate the importance of the phenylalanine
building block approach, it is useful briefly to review the gen-
eral synthetic strategies for the preparation of these types of
compounds. While attempting the synthesis of complex tar-
gets, two different strategies are usually employed.5 These
methods include linear and convergent synthetic approaches.
In the linear synthetic strategy, the target molecule is assem-
bled via a step-by-step process; while in the convergent syn-
thesis, advanced intermediates are assembled from smaller
fragments in separate sequences.
RESULTS AND DISCUSSION
In 1999, Chavan8h and coworker reported the CAN-
mediated azidoalkoxylation of enol ethers and olefins. How-
ever reaction of alkyl cinnamate with electron deficient ole-
fins was unsuccessful. The following year, Nair8b and co-
workers developed that CAN-mediated reaction of alkyl cin-
namate with sodium azide in acetonitrile followed by reac-
At an appropriate stage these intermediates are then
combined to assemble the final target. In our synthetic strat-
egy, we have pursued the phenylalanine analogs approach,
which is different from the above approaches.5 The highlight
of the phenylalanine analogs approach is the potential to pre-
pare libraries of compounds without repeating the whole syn-
thetic sequence. In Fig. 1, the shown representative examples
of phenylalanine analogs 1 are commercially available on a
large scale because they usually serve as the building blocks
R1 = H, F, MeO, (HO)2B
R2 = H, MeO
R3 = Me, Et
R1
CO2R3
R2
HN
R4 = CBZ, BOC, Fmoc
R4
1
Fig. 1.

1062 J. Chin. Chem. Soc., Vol. 52, No. 5, 2005
Chang et al.
tion with sodium acetate in dry acetone to afford the sole
(Z)-a-azidocinnamate in modest yield.8 In this paper, we
want to investigate the ambiguous CAN-mediated reaction of
alkyl cinnamate and apply the corresponding results to syn-
thesize phenylalanine analogs 1 with CBZ, BOC or Fmoc
protection.
give a-azidocinnamate 4 as a mixture of (E)- and (Z)-isomer
in two steps with moderate yield. This result is dissimilar to
Nair’s report.8b However, the generated mixture is not influ-
ential to the following reaction. In order to obtain phenyl-
alanine analogs 1, compound 4 was hydrogenated with hy-
drogen and 10% palladium on activated carbon as a catalyst
in methanol or ethanol. The corresponding amine was pro-
tected with benzylcarbonyloxy chloride (CBZCl), di-tert-butyl
dicarbonate (BOC2O) or 9-fluorenylmethyl succinimidyl
carbonate (FmocOSu) to yield phenylalanine analogs 1. Thus
a new and straightforward synthesis of phenylalanine analogs
1 was accomplished via Wittig olefination, CAN-mediated
reaction, hydrogenation and amino group protection as reac-
tion steps. Compounds 3, 4, and 1 were obtained in modest to
good yield and are shown in Table 1.
As shown in Scheme I, different benzaldehydes 2 (in-
cluded benzaldehyde, 4-methoxybenzaldehyde, 3,4-dimeth-
oxybenzaldehyde, 4-fluorobenzaldehyde and p-formylben-
zeneboronic acid) were treated with stabilized phosphorus
ylide of methyl or ethyl triphenylphosphoranylidene acetate
(Ph3P=CHCO2Me or Ph3P=CHCO2Et) in dichloromethane to
afford methyl or ethyl trans-cinnamic ester 3 in good yield.
Next, treatment of cinnamic ester 3 with sodium azide and
CAN in dry acetonitrile could provide the a-azido-b-nitrato
ester as a mixture of syn- and anti-isomers under the nitrogen
system. Without further purification, the resulting crude
product was treated with sodium acetate in dry acetone to
According to the above procedure, the synthesis of
phenylalanine analog 1e was mentioned. Among the boron
analogs, p-boronophenylalanine (BPA) is a tumor-seeking
Scheme I
(1) NaN3, CAN, MeCN
Ph3P=CHCO2R3
R1
CHO
R1
CO2R3
(2) AcONa, acetone
CH2Cl2
R2
R2
2
3
R1
(1) H2, Pd/C
R1
CO2R3
CO2R3
(2) CBZCl or BOC2O
or FmocOSu
R2
HN
R4
R2
N3
4
1
Table 1. The yieldsa of compounds 3, 4, and 1
Entry
Compound 1, R1, R2, R3, R4
3, yields (%)
3a, 95%
4, yields (%)
4a, 60%
1, yields (%)
1
2
3
4
5
6
7
8
a1, H, H, Et, CBZ
a2, H, H, Et, BOC
a3, H, H, Et, Fmoc
b1, MeO, H, Me, CBZ
b2, MeO, H, Me, BOC
b3, MeO, H, Me, Fmoc
c1, MeO, MeO, Et, CBZ
c2, MeO, MeO, Et, BOC
c3, MeO, MeO, Et, Fmoc
d1, F, H, Et, CBZ
1a1, 81%
1a2, 75%
1a3, 83%
1b1, 80%
1b2, 81%
1b3, 76%
1c1, 83%
1c2, 82%
1c3, 79%
1d1, 74%
1d2, 80%
1d3, 84%
1e, 78%
3b, 92%
3c, 87%
3d, 93%
3e, 80%
4b, 68%
4c, 66%
4d, 75%
4e, 50%
9
10
11
12
13
d2, F, H, Et, BOC
d3, F, H, Et, Fmoc
e, (HO)2B, H, Et, CBZ
a The product yield was adjusted based on isolated product.

Synthesis of Phenylalanine Analogs
J. Chin. Chem. Soc., Vol. 52, No. 5, 2005 1063
amino acid with a specific affinity for tumors and has been
used as one of the most effective boron carriers for boron-
neutron capture therapy (BNCT) of melanoma cells.13 Re-
cently, the use of BPA has been exploited for treatment of tu-
mors in clinical trials.14 Therefore, development of different
synthetic methods of BPA are important goals for synthetic
chemists and BNCT researchers.15 The racemic BPA analog
1e was transferred to L-BPA in enzymatic hydrolysis or
D,L-BPA in basic solution in previous literature reports.16
Herein we also provide a new approach for synthesizing
racemic BPA analog 1e from p-formylbenzeneboronic acid
using the CAN-mediated methodology as the key step. With
these experimental results and observations, we turned our
attention to the synthesis of azatyrosine17a and pyridyl-
alanine.17b But, the CAN-mediated reaction on the b-aro-
matic heterocyclic group (such as indole, furan and pyridine)
of the cinnamic ester was unsuccessful. We attempted to use
a variety of reaction conditions, but a complex result was still
obtained. For testing the CAN-mediated reaction on a b-ali-
phatic group (such as methyl and n-undecanyl) of the cin-
namic ester, we also found there was no reaction. The related
limitations and factors in a b-substituted group of cinnamic
ester were not clear under the CAN-mediated reaction condi-
tions.
rified by column chromatography on silica gel. All reported
temperatures are uncorrected.
General preparation of compounds 318a
A solution of benzaldehyde 2 (1.0 mmol) in methylene
chloride (10 mL) was added to a rapidly stirred solution of
Ph3P=CHCO2Me or Ph3P=CHCO2Et (1.1 mmol) in dichloro-
methane (10 mL). After the reaction mixture was stirred at rt
for 4~8 h, the resulting mixture was concentrated under re-
duced pressure. The residue was diluted with water (10 mL)
and extracted with ethyl acetate (3 ´ 30 mL). The combined
organic layers were washed with brine (2 ´ 10 mL), dried
over anhydrous magnesium sulfate, filtered, evaporated, and
purified to yield 3a~3e (80%~95%).
Ethyl cinnamate (3a)18a
IR (CHCl3) 2951, 1717 cm-1; EI-MS: C11H12O2 m/z (%)
= 176 (M+, 8); HRMS (EI, M+) calcd for C11H12O2 176.0837,
found 176.0838; 1H NMR (300 MHz, CDCl3) d 7.63 (d, J =
15.8 Hz, 1H), 7.27-7.12 (m, 5H), 6.32 (d, J = 15.8 Hz, 1H),
4.15 (q, J = 6.9 Hz, 2H), 1.31 (t, J = 6.9 Hz, 3H).
Methyl 4-methoxycinnamate (3b)18b
IR (CHCl3) 2951, 1714 cm-1; EI-MS: C11H12O3 m/z (%)
= 192 (M+, 5); HRMS (EI, M+) calcd for C11H12O3 192.0786,
found 192.0788; 1H NMR (300 MHz, CDCl3) d 7.54 (d, J =
15.9 Hz, 1H), 7.04 (d, J = 8.1 Hz, 2H), 6.82 (d, J = 8.1 Hz,
2H), 6.35 (d, J = 15.9 Hz, 1H), 3.78 (s, 3H), 3.71 (s, 3H).
In view of the experimental simplicity, we chose benz-
aldehyde as the model substrate to synthesize phenylalanine
analog 1a1. Ethyl cinnamate 3a (53 g, 0.5 mole) was chosen
as the starting material to furnish the synthesis of phenyl-
alanine analog 1a1 via four steps in moderate yield (65 g,
40%) with only one purification by column chromatography
on silica gel. The total procedure was monitored by TLC until
the reaction was complete. The overall reaction time is ap-
proximately 40 h. In conclusion, a straightforward synthesis
of phenylalanine analogs is described. The moderate reaction
scale and the relative limitation of b-substituted group of
cinnamic ester are studied. A new approach for synthesizing
racemic p-boronophenylalanine analog was also explored.
We are currently studying the related application of cerium
ammonium nitrate to other methodologies.
Ethyl 3,4-dimethoxycinnamate (3c)18a
IR (CHCl3) 2956, 1719 cm-1; EI-MS: C13H16O4 m/z (%)
= 236 (M+, 12); HRMS (EI, M+) calcd for C13H16O4 236.1049,
found 236.1047; 1H NMR (300 MHz, CDCl3) d 7.52 (d, J =
15.9 Hz, 1H), 7.07 (dd, J = 1.8, 8.2 Hz, 1H), 7.03 (d, J = 1.8
Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.23 (d, J = 15.9 Hz, 1H),
3.90 (s, 6H), 4.15 (q, J = 6.9 Hz, 2H), 1.32 (t, J = 6.9 Hz, 3H).
Ethyl 4-fluorocinnamate (3d)18a
IR (CHCl3) 2949, 1709 cm-1; EI-MS: C11H11FO2 m/z
(%) = 194 (M+, 3); HRMS (EI, M+) calcd for C11H11FO2
1
194.0743, found 194.0745; H NMR (300 MHz, CDCl3) d
EXPERIMENTAL
7.47 (d, J = 15.9 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 6.33 (d, J =
15.9 Hz, 1H), 6.30 (d, J = 8.7 Hz, 2H), 4.18 (q, J = 6.9 Hz,
2H), 1.31 (t, J = 6.9 Hz, 3H).
General
All other reagents and solvents were obtained from
commercial sources and used without further purification.
Reactions were routinely carried out under an atmosphere of
dry nitrogen with magnetic stirring. Crude products were pu-
Ethyl 4-boronocinnamate (3e)
1H NMR (300 MHz, CDCl3, CD3OD) d 7.76 (d, J = 8.2
Hz, 2H), 7.40 (d, J = 15.9 Hz, 1H), 7.24 (d, J = 8.2 Hz, 2H),

1064 J. Chin. Chem. Soc., Vol. 52, No. 5, 2005
Chang et al.
6.38 (d, J = 15.9 Hz, 1H), 4.24 (q, J = 6.9 Hz, 2H), 1.36 (t, J =
Ethyl 2-azido-3-(4-boronophenyl)acrylate (4e)
6.9 Hz, 3H).
1H NMR (300 MHz, CDCl3, CD3OD) d 7.76-7.72 (m,
2H), 7.24-7.18 (m, 2H), 6.92 (s, 1H), 4.48-4.40 (m, 2H), 1.39
(t, J = 7.0 Hz, 3H).
General preparation of compounds 48b
To a deoxygenated solution of 3 (1.0 mmol) and sodium
azide (98 mg, 1.5 mmol) in dry acetonitrile, a deoxygenated
solution of ceric ammonium nitrate (1.37 g, 2.5 mmol) in the
same solvent (10 mL) was added dropwise into an ice bath
and stirred well. On completion of the reaction it was worked
up using dichloromethane and water, then dried and concen-
trated. Without further purification, anhydrous sodium ace-
tate (123 mg, 1.5 mmol) was added to a stirred solution of the
crude residue in dry acetone (5 mL). After the reaction mix-
ture was stirred at rt for 18~22 h, the resulting mixture was
concentrated under reduced pressure. The residue was di-
luted with water (10 mL) and extracted with ethyl acetate (3 ´
20 mL). The combined organic layers were washed with
brine (2 ´ 5 mL), dried over anhydrous magnesium sulfate,
filtered, evaporated, and purified to yield 4a~4e (50%~75%).
General preparation of compounds 1
Compound 4 (0.5 mmol) was dissolved in methanol or
ethanol (10 mL) and to which was added a catalytic amount
of 10% palladium on activated carbon. Then hydrogen was
bubbled into the mixture for 10 min, and stirring occurred at
rt for 5~8 h. Filtration through a short plug of Celite and
washing with ethyl acetate (20 mL) resulted in the desired
amine. Without further purification, 0.6 mmol of benzyl chlo-
roformate (CBZCl), di-tert-butyl dicarbonate (BOC2O) or
9-fluorenylmethyl succinimidyl carbonate (FmocOSu) was
added to a stirred solution of the crude residue in dry tetra-
hydrofuran (10 mL). After the reaction mixture was stirred at
rt for 2~4 h, the resulting mixture was concentrated under re-
duced pressure. The residue was diluted with water (10 mL)
and extracted with ethyl acetate (3 ´ 20 mL). The combined
organic layers were washed with brine (2 ´ 5 mL), dried over
anhydrous magnesium sulfate, filtered, evaporated, and puri-
fied to yield 1a1~1e (74%~83%), 1a2~1d2 (75%~82%) or
1a3~1d3 (76%~84%). The 1H NMR spectral data of 1a1~1e,
1a2~1d2 and 1a3~1d3 were in accordance with commercial
authentic samples and published reports.
Ethyl 2-azido-3-phenylacrylate (4a)8b
IR (CHCl3) 3065, 1706 cm-1; EI-MS: C11H11N3O2 m/z
(%) = 217 (M+, 11); HRMS (EI, M+) calcd for C11H11N3O2
1
217.0851, found 217.0853; H NMR (300 MHz, CDCl3) d
7.84-7.81 (m, 2H), 7.40-7.33 (m, 3H), 6.93 (s, 1H), 4.38 (q, J
= 7.0 Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H).
Methyl 2-azido-3-(4-methoxyphenyl)acrylate (4b)
IR (CHCl3) 3058, 1710 cm-1; EI-MS: C11H11N3O3 m/z
(%) = 233 (M+, 8); HRMS (EI, M+) calcd for C11H11N3O3
Ethyl N-benzyloxycarbonylphenylalaninate (1a1)19a
IR (CHCl3) 3320, 1730, 1700 cm-1; EI-MS: C19H21NO4
m/z (%) = 327 (M+, 5); HRMS (EI, M+) calcd for C19H21NO4
1
1
233.0800, found 233.0801; H NMR (300 MHz, CDCl3) d
327.1471, found 327.1474; H NMR (300 MHz, CDCl3) d
7.10-7.05 (m, 2H), 6.93-6.88 (m, 3H), 3.79 (s, 3H), 3.71 (s,
3H).
7.38-7.10 (m, 10H), 5.24 (br d, J = 7.8 Hz, 1H), 5.12-5.08 (m,
2H), 4.68-4.61 (m, 1H), 4.20-4.12 (m, 2H), 3.13-3.09 (m,
2H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
171.72, 155.84, 136.51, 135.98, 129.75 (2´), 129.56 (2´),
128.77, 128.60 (2´), 127.31 (2´), 127.21, 67.17, 61.71,
55.07, 38.54, 14.31.
Ethyl 2-azido-3-(3,4-dimethoxyphenyl)acrylate (4c)
IR (CHCl3) 3060, 1704 cm-1; EI-MS: C13H15N3O4 m/z
(%) = 277 (M+, 8); HRMS (EI, M+) calcd for C13H15N3O4
1
277.1063, found 277.1065; H NMR (300 MHz, CDCl3) d
6.94 (s, 1H), 6.76-6.63 (m, 3H), 4.37 (q, J = 7.0 Hz, 2H), 3.82
(s, 6H), 1.40 (t, J = 7.0 Hz, 3H).
Methyl N-benzyloxycarbonyl-4-methoxyphenylalaninate
(1b1)19b
IR (CHCl3) 3330, 1735, 1704 cm-1; EI-MS: C19H21NO5
m/z (%) = 343 (M+, 4); HRMS (EI, M+) calcd for C19H21NO5
Ethyl 2-azido-3-(4-fluorophenyl)acrylate (4d)
IR (CHCl3) 3055, 1706 cm-1; EI-MS: C11H10FN3O2 m/z
(%) = 235 (M+, 2); HRMS (EI, M+) calcd for C11H10FN3O2
343.1420, found 343.1422; H NMR (300 MHz, CDCl3) d
1
7.40-7.28 (m, 5H), 7.00 (d, J = 6.0 Hz, 2H), 6.80 (d, J = 6.0
Hz, 2H), 5.23 (br d, J = 7.8 Hz, 1H), 5.10-5.07 (m, 2H),
4.70-4.59 (m, 1H), 3.78 (s, 3H), 3.71 (s, 3H), 3.07-3.03 (m,
2H); 13C NMR (75 MHz, CDCl3) d 172.30, 158.96, 155.87,
1
235.0757, found 235.0757; H NMR (300 MHz, CDCl3) d
7.85-7.75 (m, 2H), 7.15-6.98 (m, 2H), 6.88 (s, 1H), 4.37 (q, J
= 7.0 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H).

Synthesis of Phenylalanine Analogs
J. Chin. Chem. Soc., Vol. 52, No. 5, 2005 1065
136.51, 130.49 (2´), 128.74 (2´), 128.40 (2´), 128.30, 127.84,
114.28 (2´), 67.18, 55.43, 55.16, 52.51, 37.59.
m/z (%) = 309 (M+, 15); HRMS (EI, M+) calcd for C16H23NO5
1
309.1576, found 309.1577; H NMR (300 MHz, CDCl3) d
7.03 (d, J = 9.0 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 4.95 (br d, J
= 7.8 Hz, 1H), 4.59-4.49 (m, 1H), 3.78 (s, 3H), 3.71 (s, 3H),
3.10-2.94 (m, 2H), 1.41 (s, 9H); 13C NMR (75 MHz, CDCl3) d
172.66, 158.90, 155.32, 130.50 (2´), 128.15, 114.21 (2´),
80.11, 55.44, 54.76, 52.39, 37.70, 28.52 (3´).
Ethyl N-benzyloxycarbonyl-3,4-dimethoxyphenyl-
alaninate (1c1)
IR (CHCl3) 3333, 1738, 1703 cm-1; EI-MS: C21H25NO6
m/z (%) = 387 (M+, 4); HRMS (EI, M+) calcd for C21H25NO6
1
387.1682, found 387.1685; H NMR (300 MHz, CDCl3) d
7.35-7.30 (m, 5H), 6.75 (d, J = 9.0 Hz, 1H), 6.66-6.61 (m,
2H), 5.23 (br d, J = 7.5 Hz, 1H), 5.12-5.06 (m, 2H), 4.65-4.55
(m, 1H), 4.20-4.12 (m, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 3.18-
3.08 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 172.23, 156.36, 149.37, 148.31, 136.85, 129.11
(2´), 128.83 (2´), 122.07 (2´), 113.16, 111.97 (2´), 67.56,
62.02, 56.63 (2´), 55.36, 38.53, 14.14.
Ethyl N-tert-butoxycarbonyl-3,4-dimethoxyphenyl-
alaninate (1c2)20c
IR (CHCl3) 3395, 1746, 1704 cm-1; EI-MS: C18H27NO6
m/z (%) = 353 (M+, 8); HRMS (EI, M+) calcd for C18H27NO6
1
353.1838, found 353.1840; H NMR (300 MHz, CDCl3) d
6.78 (d, J = 6.0 Hz, 1H), 6.68-6.62 (m, 2H), 4.97 (br d, J = 7.8
Hz, 1H), 4.54-4.48 (m, 1H), 4.16 (q, J = 6.0 Hz, 2H), 3.85 (s,
6H), 3.10-2.95 (m, 2H), 1.41 (s, 9H), 1.24 (t, J = 6.0 Hz, 3H);
13C NMR (75 MHz, CDCl3) d 172.17, 155.31, 149.08, 148.32,
128.74, 121.68, 112.70, 111.45, 80.07, 61.53, 56.11, 56.03,
54.74, 38.13, 28.54 (3´), 14.39.
Ethyl N-benzyloxycarbonyl-4-fluorophenylalaninate
(1d1)19c
IR (CHCl3) 3342, 1740, 1710 cm-1; EI-MS: C19H20FNO4
m/z (%) = 345 (M+, 1); HRMS (EI, M+) calcd for C19H20FNO4
1
345.1376, found 345.1375; H NMR (300 MHz, CDCl3) d
Ethyl N-tert-butoxycarbonyl-4-fluorophenylalaninate
(1d2)
7.36-7.26 (m, 5H), 7.08-7.03 (m, 2H), 6.98-6.91 (m, 2H),
5.25 (br d, J = 7.8 Hz, 1H), 5.12-5.08 (m, 2H), 4.63-4.58 (m,
1H), 4.19-4.13 (m, 2H), 3.16-3.04 (m, 2H), 1.23 (t, J = 7.2
Hz, 3H); 13C NMR (75 MHz, CDCl3) d 171.53, 163.87,
160.62, 155.78, 136.46, 131.12, 131.01, 128.76, 128.46 (2´),
128.34 (2´), 115.76, 115.47, 67.22, 61.82, 55.06, 37.79,
14.33.
IR (CHCl3) 3386, 1745, 1711 cm-1; EI-MS: C16H22FNO4
m/z (%) = 311 (M+, 5); HRMS (EI, M+) calcd for C16H22FNO4
1
311.1533, found 311.1533; H NMR (300 MHz, CDCl3) d
7.12-7.07 (m, 2H), 7.00-6.94 (m, 2H), 4.99 (br d, J = 6.0 Hz,
1H), 4.59-4.50 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.14-3.00
(m, 2H), 1.41 (s, 9H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR (75
MHz, CDCl3) d 172.94, 163.83, 130.59, 155.24, 132.09,
131.02, 115.68, 115.40, 80.19, 61.64, 54.70, 37.91, 28.51
(3´), 14.35.
Ethyl N-benzyloxycarbonyl-4-boronophenylalaninate (1e)
1H NMR (300 MHz, CDCl3, CD3OD) d 7.76-7.72 (m,
2H), 7.36-7.26 (m, 5H), 7.14-7.08 (m, 2H), 5.26-5.22 (m,
1H), 5.10-5.07 (m, 2H), 4.48-4.40 (m, 3H), 3.09-2.98 (m,
2H), 1.39 (t, J = 7.0 Hz, 3H).
Ethyl N-9-fluorenylmethoxycarbonylphenylalaninate
(1a3)21
IR (CHCl3) 3420, 1734, 1717 cm-1; EI-MS: C26H25NO4
m/z (%) = 415 (M+, 2); HRMS (EI, M+) calcd for C26H25NO4
Ethyl N-tert-butoxycarbonylphenylalaninate (1a2)20a
IR (CHCl3) 3397, 1740, 1704 cm-1; EI-MS: C16H23NO4
m/z (%) = 293 (M+, 12); HRMS (EI, M+) calcd for C16H23NO4
1
415.1784, found 415.1786; H NMR (300 MHz, CDCl3) d
7.66 (d, J = 7.4 Hz, 2H), 7.50-7.45 (m, 2H), 7.34-7.14 (m,
7H), 7.03 (d, J = 5.9 Hz, 2H), 5.22 (d, J = 8.0 Hz, 1H), 4.57 (d,
J = 6.0 Hz, 1H), 4.39-4.02 (m, 5H), 3.04-3.00 (m, 2H), 1.14
(t, J = 7.2 Hz, 3H).
1
293.1627, found 293.1625; H NMR (300 MHz, CDCl3) d
7.31-7.12 (m, 5H), 4.98 (br d, J = 6.6 Hz, 1H), 4.59-4.53 (m,
1H), 4.15 (q, J = 7.2 Hz, 2H), 3.14-3.04 (m, 2H), 1.41 (s, 9H),
1.22 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 172.11,
155.32, 136.32, 129.59 (2´), 128.71 (2´), 127.20, 80.09,
61.54, 54.67, 38.64, 28.52 (3´), 14.33.
Methyl N-9-fluorenylmethoxycarbonyl-4-methoxyphenyl-
alaninate (1b3)
IR (CHCl3) 3422, 1733, 1715 cm-1; EI-MS: C26H25NO5
m/z (%) = 431 (M+, 5); HRMS (EI, M+) calcd for C26H25NO5
Methyl N-tert-butoxycarbonyl-4-methoxyphenylalaninate
(1b2)20b
1
431.1733, found 431.1735; H NMR (300 MHz, CDCl3) d
IR (CHCl3) 3389, 1744, 1706 cm-1; EI-MS: C16H23NO5
7.76 (d, J = 7.5 Hz, 2H), 7.59-7.56 (m, 2H), 7.35-7.31 (m,

1066 J. Chin. Chem. Soc., Vol. 52, No. 5, 2005
Chang et al.
Nolan, W. P.; Ratcliffe, G. S.; Rees, D. C. Tetrahedron Lett.
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2H), 7.13 (d, J = 7.0 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.81 (d,
J = 8.0 Hz, 2H), 5.26 (d, J = 8.0 Hz, 1H), 4.52-4.48 (m, 1H),
4.44-4.21 (m, 3H), 3.78 (s, 3H), 3.71 (s, 3H), 3.08-3.00 (m,
2H).
3. (a) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl.
1993, 32, 1244. (b) Liskamp, R. M. J. Trav. Chim. Pays-Bas
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Ethyl N-9-fluorenylmethoxycarbonyl-3,4-dimethoxy-
phenylalaninate (1c3)
IR (CHCl3) 3425, 1730, 1715 cm-1; EI-MS: C28H29NO6
m/z (%) = 475 (M+, 2); HRMS (EI, M+) calcd for C28H29NO6
1
475.1995, found 475.1996; H NMR (300 MHz, CDCl3) d
7.76 (d, J = 7.5 Hz, 2H), 7.59-7.54 (m, 2H), 7.40 (d, J = 7.5
Hz, 2H), 7.30 (d, J = 7.5 Hz, 2H), 6.77 (d, J = 7.0 Hz, 1H),
6.71-6.68 (m, 2H), 5.29 (d, J = 8.0 Hz, 1H), 4.70-4.54 (m,
1H), 4.39-4.20 (m, 5H), 3.58 (s, 6H), 3.1-3.01 (m, 2H), 1.16
(t, J = 7.2 Hz, 3H).
Ethyl N-9-fluorenylmethoxycarbonyl-4-fluorophenyl-
alaninate (1d3)
IR (CHCl3) 3430, 1742, 1722 cm-1; EI-MS: C26H24FNO4
m/z (%) = 433 (M+, 1); HRMS (EI, M+) calcd for C26H24FNO4
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1
433.1689, found 433.1688; H NMR (300 MHz, CDCl3) d
7.75 (d, J = 7.5 Hz, 2H), 7.60 (d, J = 7.5 Hz, 2H), 7.56 (d, J =
7.5 Hz, 2H), 7.39 (d, J = 7.5 Hz, 2H), 7.32-7.28 (m, 2H),
7.25-7.21 (m, 2H), 5.37 (d, J = 8.5 Hz, 1H), 4.67-4.62 (m,
1H), 4.49-4.17 (m, 5H), 3.20-3.08 (m, 2H), 1.16 (t, J = 7.2
Hz, 3H).
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ACKNOWLEDGEMENTS
The authors would like to thank the National Science
Council (NSC 94-2113-M-390-001) of the Republic of China
for financial support.
Received March 11, 2005.
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