CHEM. RES.

CHINESE UNIVERSITIES 2011, 27(2), 224227

Novel Method for Selective Debenzylation

Under Maintenance of Fluoro Atom
Substituted on -Amino Acids

ZHENG Yi1, WU Gang2, ZHU Xin-rong2, LI Yue-jie2, MA Yu-heng2, ZHAO Xin2,

LU Tao1* and ZHU Yong-qiang2*
1. School of Basic Sciences, China Pharmaceutical University, Nanjing 210009, P. R. China;
2. Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research,
Jiangsu Simcere Pharmaceutical Research Institute, Nanjing 210042, P. R. China

Abstract tert-Butyl (R)-3-amino-3-(3-fluorophenyl)propanoate(5) was prepared with conventional debenzylation

method. However, the tert-butyl (R)-3-[(S)-1-phenylethyl-amino]-3-(3-fluorophenyl) propanoate(6) and tert-butyl
(R)-3-amino-3-phenylpropanoate(7) were generated as the byproducts under the general catalytic hydrogenation
Pd(OH)2/C-H2 conditions. So a series of experiments was performed to optimize the reaction conditions so that
product 5 could be obtained with high purity and yield. Finally an effective catalytic system, Pd/C-HCOOH-CH3OH,
was discovered.
Keywords -Amino acid; Debenzylation; Defluorination; Catalytic hydrogenation
Article ID 1005-9040(2011)-02-224-04

1 Introduction ester was also removed by Pd(OH)2/C-CH3OH-H2 catalytic

Nowadays, more and more attention has been paid to the
synthesis of -amino acids, especially the chiral ones. -Amino
acids are the components of natural products with good phar-
macological activities. For example, -hydroxy--phenylala-
nine, an important component of taxol[1], was found to be es-
sential to its anti-tumour activity[24]. In edeine A, one key
component was found to be (S)--tyrosine[5].
The biological properties of peptides constructed from
-amino acids differ from those composed of -amino acids
due to their different dimensions, geometries, and polarities. It
has been shown that they do not bind to the active sites of pep-
tidases and are not vulnerable to be degraded[6,7] by other hy-
drolytic and metabolizing enzymes in mammals[8], insects[9],
plants, and even in microorganisms[10]. In our previous work,
we found that racemic -amino acids composed of dipeptidyl
boronic acids were potent and selective 20S proteasome inhi-
bitors[11]. In order to thoroughly and deeply investigate the
function of stereoisomers, some chiral -amino acid building
blocks are in great need.
Benzyl group was used as the protecting group in our
synthesis of chiral -amino acid substituted by fluoro atom for
it could be easily introduced and removed under mild condi-
tions. For the preparation of fluoro substituted chiral -amino
acid ester, Pd(OH)2/C was used as a catalyst for debenzylation
in the presence of H2. However, an interesting result was ob-
tained: the fluoro atom on the aromatic ring of -amino acid
system. CX bond(X=Cl, Br) can be activated by some re-
ductants such as NaBH4, H2, HCOOH and the halogen
atoms(Cl, Br) may be removed readily. Iodine atoms can be
easily removed in the presence of some acid or base, such as
hydrochloric acid and sodium methoxide[12,13], on the contrary,
the removal of fluoro atoms is difficult. It was reported that
CF bond could be activated only by several reductants such
as zinc of pentafluoro-benzonitrile[14] and Ti(III)-citrate[15].
Furthermore, no literature reported that the fluoro atoms could
be removed under the condition of Pd(OH)2/C-CH3OH-H2
system, which was frequently used to remove the benzyl group
in our team. To avoid this side reaction, we carried out a series
of experiments to optimize the conditions to obtain the chiral
-amino acid substituted by fluoro atoms.
2 Results and Discussion
Scheme 1 shows the synthesis of fluoro substituted chiral
-amino acid according to the reported literature[1618].
The commercially available 3-fluoro-benzaldehyde was treated
with n-BuLi and tert-butyl diethylphosphonoacetate(1) at
80 C, giving ,-unsaturated tert-butyl ester(2) in a high
yield.
The coupled reaction was carried out between ester 2 and
the homochiral (S)-N-benzyl-N-(-methylbenzyl) amine(3) in
the presence of n-BuLi at 80 C to produce chiral -amino
acid ester(4) in a high yield. Compound 4 was an important
intermediate, which was debenzylated to give ester 5 which

*Corresponding author. E-mail: lutao@cpu.edu.cn; zhyqscu@hotmail.com

Received May 21, 2010; accepted October 7, 2010.
Supported by the National Key New Drug Creation Program of China(No.2009ZX09103-001) and the Jiangsu Key Labora-
tory of Molecular Targeted Antitumor Drug Research Foundation, China(No.BM2008201).
No.2 ZHENG Yi et al. 225
was saponificated and the desired -amino acid (R)-3-amino- during the process of debenzylation with the Pd(OH)2/
3-(3-fluorophenyl)propanoic acid was obtained. However, it C-CH3OH-H2 catalytic system.
was found that two byproducts 6 and 7 were also obtained

Scheme 1 General synthetic route of chiral -amino acid ester(5)

Reagents and conditions: i. (EtO)2POCH2CO2tBu, n-BuLi, THF, 80 C to r. t., 87%; ii. 3, n-BuLi, THF, 80 C, 4 h, 70%;
iii. Pd(OH)2/C, H2, CH3OH, r.t., 24 h.
Compound 6 was the product by deprotecting one benzyl
group of compound 4, while byproduct 7 was formed by re- 2.2 Catalyst Effect
moving benzyl and fluoro groups. We did not obtain compound
We also investigated the roles of various catalysts on the
5 as the only product under the condition of Pd(OH)2/
activity and selectivity of the reaction since catalysts always
C-CH3OH-H2 system, and there were always different percen-
have great effect on organic reactions[19]. The results are listed
tages of compounds 5, 6 and 7. To obtain the chiral ester 5 in
in Table 2, from which it can be deduced that different catalysts
high purity and yield, different solvents, catalysts and hydrogen
have great influence on the selectivity and activity of the de-
donors were screened.
benzylation reaction. Among the catalysts used for reductive
debenzylation, we did not obtain any compound 5, 6 or 7 with
2.1 Solvent Effect
p-toluene sulfonic acid(PTSA) or BBr3[20]. The catalytic activi-
Firstly, the effects of different solvents were investigated ty and selectivity of Pd/C was much higher than those of
with the results listed in Table 1. From Table 1, it can be con- Pd(OH)2/C, with a much higher percentage of compound 5 and
cluded that solvents have great influence on the selectivity and less reaction time. However, byproduct 7 could be detected in
activity to the catalytic debenzylation of compound 4. Of the both the systems in the presence of Pd/C or Pd(OH)2/C. Per-
protic solvents, acetic acid produced a high percentage of haps changing the hydrogen donors of Pd/C catalytic system
compound 5 but a little ones of compounds 6 and 7 at the same will produce compound 5 as the only product[2123]. The cata-
time. The percentage of byproduct 6 was much higher than that lysts used for oxidative debenzylation were not as good as
of compound 5 in isopropanol while no compound 7 was de- those for the reductive ones. With 2,3-dichloro-5,6-dicyano-
tected. Compound 5 was produced as the major product and 1,4-benzoquinone(DDQ) as the catalyst, only compound 6
compounds 6, 7 as the minor products in the reaction of me- could be detected. Ceric ammonium nitrate(CAN)[24,25] with
thanol and ethanol. Of the aprotic solvents, ethyl acetate(EA) solvent CH3CN-H2O or CH3OH-H2O gave compound 6 as the
was the best one, which produced 80% of compound 5 and major product and compound 5 as the minor one.
20% of compound 6. In tetrahydrofuran(THF), only 8.3% of Table 2 Influences of catalysts on the reaction
compound 5 was obtained with more than 90% of compound 6 Reaction Ratio of
Catalyst Solvent Temperature
and no compound 7. For ether solvent, the result was not satis- time/h 5:6:7a
fying. In general, no ideal results were obtained by varying the DDQb CH3OH-H2Oe r.t. 72 0:1:0
CANc CH3CN-H2Oe r.t. 20 1:32:0
solvents in the selected catalytic system. Subsequently we
CANc CH3OH-H2Oe r.t. 72 1:37:0
screened other catalysts to get product 5 in a much higher d
PTSA Toluene Reflux 48 n.r.f
yield .
BBr3 CH2Cl2 80C 24 n.r
Table 1 Influence of solvents on the reactiona Pd(OH)2/C CH3OH r.t. 24 8:1:2
Solvent Ratio of 5:6:7b Solvent Ratio of 5:6:7b Pd/C CH3OH r.t. 4 30:0:1
MeOH 8:1:2 THF d
1:11:0 a. Ratios of the products were determined by LC-MS; b. DDQ:
EtOH 6:1:1 EAe 4:1:0 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; c. CAN: ceric ammonium
IPAc 1:5:0 Et2Of 5:4:1 nitrate; d. PTSA: p-toluene sulfonic acid; e. the volume ratio of CH3OH
(CH3CN) to H2O is 10:2; f. n.r.: not reaction.
AcOH 14:1:1
a. Experimental conditions: Pd(OH)2/C(30 mg, 0.021 mmol, 15% mass
fraction of compound 4); solvent(10 mL); H2, 24 h, r.t.; b. ratios of the
2.3 Hydrogen Donor Effect
products were determined by LC-MS; c. IPA: isopropyl alcohol; d. THF: Finally, the effects of hydrogen donors on the reaction
tetrahydrofuran; e. EA: ethyl acetate; f. Et2O: diethyl ether.
226 CHEM. RES. CHINESE UNIVERSITIES
were investigated with the results listed in Table 3. It shows
that HCOOH was the best one, and it took the least time and
gave product 5 in a high yield. For HCOONH4, it produced
62% of compound 5, 31% of compound 6 and 7% of
compound 7. In conclusion, Pd/C-HCOOH-CH3OH was the
most active and selective system for the debenzylation of
compound 4 to obtain product 5 with high purity and yield.
Table 3 Influences of hydrogen donors on the reactiona
Hydrogen donor Reaction time/h Ratio of 5:6:7b
H2 4 30:0:1
HCOONH4 10 8:4:1
HCOOH 0.5 1:0:0
a. Experimental conditions: Pd/C(30 mg, 0.028 mmol, 15% mass frac-
tion of compound 4); CH3OH(10 mL); r.t.; b. ratios of the products were
determined by LC-MS.
3 Experimental
3.1 Apparatus and Materials
Commercially available reagents were used directly
without any purification unless otherwise stated. tert-Butyl
diethylphosphonoacetate(1) was supplied by Alfa Aesar Chi-
na(Tianjin) Co., Ltd. Pd/C(10% Pd, reduced, wet) and
Pd(OH)2/C were supplied by J&K China Chemical Ltd.
n-Butyllithium(2.5 mol/L solution in hexanes) was supplied by
Acros Organics. Absolutely anhydrous solvents were obtained
with the proper methods introduced in the literature. Yields
referred to chromatographical ones unless otherwise stated.
Reactions were monitored by thin-layer chromatography
carried out on silica gel aluminium sheets(60F-254) and RP-18
F254s with UV light as a visualizing agent. Column chromato-
graphy was performed on 200300 mesh silica gel. Analytical
reverse phase HPLC was run on a Kromasil 100-5 C18, 4.6
mm250 mm column eluted with a mixture of methanol and
water containing 0.02% triethylamine and 0.03% trifluoacetic
acid. 1H and 13C NMR spectra were recorded at room tempera-
ture on a Brucker Avance 300 or Avance 500 spectrometer.
Chemical shifts were reported in ppm( units) and tetramethyl-
silane(TMS) was used as internal reference. Coupling con-
stants(J) were expressed in Hz. Mass spectra were obtained on
an Agilent LC-MS(1956B) instrument in electrospray positive
and negative ionization modes.
3.2 General Procedure for Preparing Compound 4
tert-Butyl diethylphosphonoacetate(1, 27.75 g, 0.11 mol)
was dissolved in 45 mL of anhydrous THF under a nitrogen
atmosphere at 80 C. The mixture was stirred for 2 h after
n-BuLi(52 mL, 2.5 mol/L, 0.13 mol) was added dropwise. The
3-fluoro-benzaldehyde(12.4 g, 0.1 mol)-THF solution(10 mL)
was added into the mixture dropwise. After stirring at 80 C
for 6 h, saturated aqueous solution of NH4Cl was added to
quench the reaction.
The solution was washed with 300 mL of brine and
extracted with CH2Cl2. The organic layer was dried over an-
hydrous Na2SO4. After filtration, the solvent was evaporated to
dryness, and a yellow oil was obtained, which was purified by
column chromatography then tert-butyl (E)-3-(3-fluorophenyl)
Vol.27
acrylate(2) was obtained(19.37 g, 87%).
(S)-N-Benzyl-1-phenylethanamine(3, 21 g, 0.1 mol) was
dissolved in 60 mL of anhydrous THF under a nitrogen atmos-
phere at 80 C. n-BuLi(48 mL, 2.5 mol/L, 0.12 mol) was
added dropwise to it and the mixture was stirred for 2.5 h. An-
hydrous THF solution(30 mL) of compound 2(13.9 g, 62.5
mmol) was added in the above reaction system dropwise. The
solution was stirred at 80 C for 5 h, then it was quenched by
the addition of saturated aqueous solution of NH4Cl and parti-
tioned between brine and cyclohexane. After being dried over
Na2SO4 and concentrated in vacuo, a yellow oil was obtained,
which was purified by column chromatography and compound
4 was obtained(18.88 g).
tert-Butyl (R)-3-{benzyl-[(S)-1-phenylethyl]-amino}-3-(3-
fluorophenyl)propanoate(4): yield 70%. D = 12.2(c=1.0,
CHCl3). 1H NMR(500 MHz, CDCl3), : 1.25(CH3, s, 9H),
1.28(CH3, d, J=6.5 Hz, 3H), 2.442.69(CH2, m, 2H),
3.67(CH2, s, 2H), 3.97(CH, q, J=7.0 Hz, 1H), 4.41(CH,
dd, J=5.5, 10.0 Hz, 1H), 6.916.95(Ph, m, 1H), 7.12
7.15(Ph, m, 1H), 7.177.19(Ph, m, 2H), 7.217.29(Ph, m,
6H), 7.32(Ph, t, J=7.5 Hz, 2H), 7.40(Ph, d, J=7.5 Hz, 2H);
13
C NMR(125 MHz, CDCl3), : 27.8, 27.9, 37.9, 51.0, 57.4,
59.0, 77.0, 114.0, 115.2, 126.6, 127.0, 127.8, 128.0, 128.2,
129.4, 129.5, 143.8, 163.8, 170.9. MS(ESI), m/z: 456.1
([M+Na]+, 100%), 434.1([M+H]+, 57%).
3.3 General Procedure for Preparing Compound 5
Compound 4(200 mg, 0.46 mmol) and Pd/C(30 mg, 0.028
mmol, 15% mass fraction of compound 4) were added in 10
mL of 4.4% HCOOH-CH3OH mixture. The mixture was stirred
under a nitrogen atmosphere for 0.5 h. After Pd/C was removed,
the reaction solution was washed with saturated aqueous solu-
tion of NaHCO3 and extracted with EA. The organic layer was
dried over anhydrous Na2SO4. After the desiccant and the sol-
vent were removed, compound 5 was obtained(yellow oil, 101
mg).
tert-Butyl (R)-3-amino-3-(3-fluorophenyl)propanoate(5):
yield 91.9%. D =+10.1(c=1.0, CHCl3){ D =+11.6(c=
1.0, CHCl3) in Ref. [26]}. 1H NMR(500 MHz, DMSO-d6), :
1.301.36(CH3, m, 9H), 2.50(CH2, dd, J=7.5, 12.0 Hz,
2H), 4.16(CH, t, J=7.0 Hz, 1H), 7.007.04(Ph, m, 1H),
7.177.21(Ph, m, 2H), 7.307.35(Ph, m, 1H); 13C NMR(125
MHz, DMSO-d6), : 27.6, 45.1, 52.4, 79.6, 113.1, 122.5, 129.8,
148.9, 163.1, 170.2. MS(ESI), m/z 262.1([M+Na]+, 7%), 240.1
([M+H]+, 20%).
3.4 General Procedure for Preparing Compounds
6 and 7
A mixture of compound 4(200 mg, 0.46 mmol),
Pd(OH)2/C(30 mg, 0.021 mmol, 15% mass fraction of 4) was
added in 10 mL of CH3OH to which hydrogen was charged.
After stirring for 24 h, the reaction solution was filtered to re-
move Pd(OH)2/C and concentrated in vacuo, a yellow oil was
obtained, which was purified by column chromatography to
give compounds 5(68.8 mg), 6(yellow oil, 13.5 mg) and 7
(yellow oil, 15.5 mg).
No.2 ZHENG Yi et al.
tert-Butyl(R)-3-[(S)-1-phenylethyl-amino]-3-(3-fluorophen-
yl)propanoate(6): yield 8.6%. D = 17.6(c=1.0, CHCl3).
1
H NMR(500 MHz, CDCl3), : 1.331.35(CH3, m, 3H),
1.361.38(CH3, m, 9H), 2.57(CH2, dd, J=6.5, 19.5 Hz,
2H), 3.67(CH, q, J=6.5 Hz, 1H), 4.12(CH, dd, J=5.2, 8.0
Hz, 1H), 6.886.92(Ph, m, 1H), 6.987.01(Ph, m, 1H),
7.03(Ph, d, J=7.5 Hz, 1H), 7.177.21(Ph, m, 1H), 7.237.29
(Ph, m, 5H); 13C NMR(125 MHz, CDCl3), : 22.5, 28.0, 43.6,
54.8, 56.9, 77.0, 113.9, 114.1, 122.7, 126.6, 126.9, 128.4,
129.8, 145.7, 163.9, 170.7. MS(ESI), m/z: 366.1([M+H]+,
100%), 344.2([M+Na]+, 42%).
tert-Butyl(R)-3-amino-3-phenylpropanoate(7): yield 15.2%.
D =+13.1(c=1.0, CHCl3){ D =+20.0(c=0.71, CHCl3) in
Ref.[27]}. 1H NMR(500 MHz, DMSO-d6), : 1.301.33
(CH3, m, 9H), 2.48(CH2, dd, J=6.5, 14.5 Hz, 2H),
4.15(CH, t, J=7.0 Hz, 1H), 7.197.22(Ph, m, 1H),
7.267.31(Ph, m, 2H), 7.347.37(Ph, m, 2H); 13C NMR(125
MHz, DMSO-d6), : 27.6, 45.2, 52.8, 79.5, 125.9, 126.4, 126.6,
128.0, 128.2, 145.5, 170.3. MS(ESI), m/z: 244.1([M+Na]+,
16%), 222.1([M+H]+, 42%).
4 Conclusions
In summary, a series of experiments was performed to
screen the conditions to remove the benzyl group while keeping
fluoro atom of the -amino acid. An optimized condition of
HCOOH-Pd/C-CH3OH catalytic system was found, under
which tert-butyl (R)-3-amino-3-(3-fluorophenyl)propanoate(5)
could be obtained with high purity and yield and the desired
-amino acid could be produced by subsequent saponification.
References
[1] Cardillo G., Gentilucci L., Tolomelli A., Tomasini C., J. Org.
Chem., 1998, 63, 2351
[2] Wani M. C., Taylor H. L., Wall M. E., Coggon P., McPhail A. T., J.
Am. Chem. Soc., 1971, 93, 2325
[3] Chen Y., Zhou Y. L., Ren Y., Yan W. Q., Chem. Res. Chinese
Universities, 2005, 21(6), 749
[4] Shi B. X., Liang S. L., Yuan Y. J., Sun M., Miao F. M., Chem. J.
Chinese Universities, 2000, 21(3), 401
[5] Hettinger T. P., Craig C. L., Biochemistry, 1968, 7, 4147
[6] Frackenpohl J., Arvidsson P. I., Schreiber J. V., Seebach D., Chem.
227
Bio. Chem, 2001, 2, 445
[7] Seebacha D., Abele S., Schreiber J. V., Martinoni B., Nussbaum
A.K., Schild H., Schulz H., Hennecke H., Woessner R., Bitsch F.,
Chimia, 1998, 52, 734
[8] Weiss H. M., Wirz B., Schweitzer A., Amstutz R., Rodriguez-
Perez M. I., Andres H., Metz Y., Gardiner J., Seebach D., Chem.
Biodiversity, 2007, 4, 1413
[9] Lind R., Greenhow D., Perry S., Kimmerlin T., Seebach D., Chem.
Biodiversity, 2004, 1, 1391
[10] Seebach D., Namoto K., Mahajan Y. R., Bindschadler P., Sustmann
R., Kirsch M., Ryder N. S., Weiss M., Sauer M., Roth C., Werner
S., Beer H. D., Mundling C., Walde P., Voser M., Chem. Biodiver-
sity, 2004, 1, 65
[11] Zhu Y. Q., Zhu X. R., Wu G., Ma Y. H., Li Y. J., Zhao X., Yuan Y.
X., Yang J., Yu S., Shao F., Li R. T., Ke Y. R., Lu A. J., Liu Z. M.,
Zhang L. R., J. Med. Chem., 2010, 53, 1990
[12] Jorgensen E. C., Reid J. A. W., J. Org. Chem., 1964, 29, 3396
[13] Tomaselli G. A., Bunnett J. F., J. Org. Chem., 1992, 57, 2710
[14] Laev S. S., Shteingart V. D., Tetrahedron Lett., 1997, 38, 3765
[15] Ochoa-Herrera V., Sierra-Alvarez R., Somogyi A., Jacobsen N. E.,
Wysocki V. H., Field J. A., Environ. Sci. Technol., 2008, 42, 3260
[16] Davies S. G., Garrido N. M., Kruchinin D., Ichihara O., Kotchie L.
J., Price P. D., Mortimer A. J. P., Russell A. J., Smith A. D.,
Tetrahedron: Asymmetr., 2006, 17, 1793
[17] Davies S. G., Mulvaney A. W., Russell A. J., Smith A. D., Tetra-
hedron: Asymmetr., 2007, 18, 1554
[18] Cheng C. J., Sun J. W., Xing L. X., Xu J. M., Wang X. Y., Hu Y.
F., J. Org. Chem., 2009, 74, 5671
[19] Studer M., Blaser H. U., J. Mol. Catal. A: Chem., 1996, 112, 437
[20] Paliakov E., Strekowski L., Tetrahedron Lett., 2004, 45, 4093
[21] David A., Vannice M. A., J. Catal., 2006, 237, 349
[22] Rajagopal S., Spatola A. F., Appl. Catal. A: Gen., 1997, 152, 69
[23] Elamin B., Anantharamaiah G. M., Royer G. P., Means G. E., J.
Org. Chem., 1979, 44, 3442
[24] Bull S. D., Davies S. G., Fenton G., Mulvaney A. W., Prasad R. S.,
Smith A. D., Chem. Comm., 2000, 5, 337
[25] Murakata C., Ogawa T., Carbohyd. Res., 1992, 234, 75
[26] Bull S. D.,. Davies S. G., Delgado-Ballester S., Kelly P. M., Kot-
chie L. J., Gianotti M., Laderas M., Smith A. D., J. Chem. Soc.,
Perkin Trans. 1, 2001, 23, 3112
[27] Sakai T., Doi H., Tomioka K., Tetrahedron, 2006, 62, 8351