A concise synthesis of enantiomerically pure L-(4-Boronophenyl)alanine from L-tyrosine

Full text of DOI:10.1021/jo980818r

J . Org. Chem. 1998, 63, 7529-7530
7529
A Con cise Syn th esis of En a n tiom er ica lly
Sch em e 1
P u r e L-(4-Bor on op h en yl)a la n in e fr om
L-Tyr osin e
Hiroyuki Nakamura, Masaru Fujiwara, and
Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science,
Tohoku University, Sendai 980-8578, J apan
Received April 30, 1998
1
(
4-Boronophenyl)alanine (BPA) is a practical boron
compound, which is clinically used not only for the
treatment of malignant melanoma but also for that of
1
-3
brain tumors, on neutron capture therapy (NCT).
was developed by Miyaura, is a direct procedure for the
synthesis of arylboronic esters from haloarenes (eq 2).
4
9
Since Mishima and co-workers revealed that the L-form
of BPA is more efficiently incorporated into melanoma
cells than the racemic one, the enantioselective synthesis
of L-BPA has been required. Enriched L-BPA was
prepared enzymatically through R-chymotrypsin hydroly-
5
sis of the ethyl ester of racemic BPA synthesized by the
traditional method.1
,6
In this case, 50% of another
enantiomer (D-BPA) was recovered from the racemic
material. Recently, two synthetic routes of L-BPA were
reported. An asymmetric hydrogenation route gave
L-BPA with enantiomeric excess of up to 88% (96% ee
after recrystallization).7 Another route using palladium-
catalyzed coupling reaction of (iodophenyl)boronate with
the chiral organozinc derived from L-serine needed rather
lengthy synthetic steps.8 Herein we report a concise
synthesis of enantiomerically pure L-BPA from L-tyrosine
using palladium-catalyzed carbon-boron bond formation
reaction (eq 1).
Triflate 2 was readily prepared from L-tyrosine by the
literature procedure.10 The cross-coupling reaction of the
triflate 2 with 1a in dioxane proceeded very smoothly in
a catalytic amount of PdCl (dppf) (1,1′-bis(diphenylphos-
2
phino)ferrocene), giving the corresponding arylboronic
ester 3a in quantitative yield. However, subsequent
1
1
hydrolysis of pinacol ester 3a with NaIO4 gave an
unseparable mixture of the boronic acid 4 and unidenti-
fied materials12 (Scheme 1). The removal of the Cbz
(carbobenzoxy) protecting group by the treatment of 4
with either Pd catalyst/H2 or acidic reagents gave a
mixture of the desired product (L-BPA) and unidentified
materials, and separation of L-BPA from the mixture was
difficult. The other hydrolysis method, based on trans-
esterification with phenylboronic acid, was not effective
for arylboronic ester 3a .11
Thus, 1,3-diphenyl-1,3-propanediol (5) was chosen as
an ester group of diboron since the boronic ester derived
Resu lts a n d Discu ssion
(4) (a) Mishima, Y.; Honda, C.; Ichihashi, M.; Obara, H.; Hiratsuka,
J .; Fukuda, H.; Karashima, H.; Kobayashi, T.; Kanda, K.; Yoshino, K.
Lancet 1989, 388. (b) Mishima, Y.; Ichihashi, M.; Hatta, S.; Honda,
C.; Yamamura, K.; Nakagawa, T. Pigm. Cell Res. 1989, 5, 226.
Palladium-catalyzed cross-coupling reaction of the
pinacol ester of diboronic acid 1a with haloarenes, which
(5) Roberts, D. C.; Suda, K.; Samanen, J .; Kemp, D. S. Tetrahedron
Lett. 1980, 21, 3435.
(6) Kirihata, M.; Morimoto, T.; Ichimoto, I. Biosci. Biotech. Biochem.
1993, 57, 1940.
(7) Samsel, E. G. U.S. Patent 5157149, 1992; Chem. Abstr. 1993,
118, 125073.
(8) Malan, C.; Morin, C. Synlett 1996, 167.
(9) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J . Org. Chem. 1995,
60, 7508. (b) Murata, M.; Watanabe, S.; Masuda, Y. J . Org. Chem.
1997, 62, 6458. (c) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457
and references therein.
(
1) Snyder, H. R.; Reedy, A. J .; Lennarz, W. M. J . J . Am. Chem.
Soc. 1958, 80, 835.
2) (a) Locher, G. L. Am. J . Roentgenol. 1936, 36, 1. For recent
reviews, see: (b) Hawthorn, M. F. Angew. Chem., Int. Ed. Engl. 1993,
2, 950. (c) Yamamoto, Y. Pure Appl. Chem. 1991, 63, 423. (d) Barth,
(
3
R. F.; Soloway, A. H.; Fairchild, R. G. Cancer Res. 1990, 50, 1061. (e)
Soloway, A. H.; Tjarks, W.; Barnum, B. A.; Rong, F.-G.; Barth, R. F.;
Wyzlic, I. M.; Wilson, J . G. Chem. Rev. 1998, 98, 1515.
(3) For our recent papers on NCT, see: (a) Yamamoto, Y.; Seko, T.;
Nakamura, H.; Nemoto, H.; Hojo, H.; Mukai, N.; Hashimoto, Y. J .
Chem. Soc., Chem. Commun. 1992, 157. (b) Yamamoto, Y.; Seko, T.;
Nakamura H.; Nemoto, H. Heteroatom Chem. 1992, 3, 239. (c) Nemoto,
H.; Wilson, J . G.; Nakamura, H.; Yamamoto, Y. J . Org. Chem. 1992,
(10) Wang, W.; Obeyesekere, N. U.; McMurray, J . S. Tetrahedron
Lett. 1996, 37, 6661.
(11) Coutts, S. J .; Adams, J .; Krolikowski, D.; Snow, R. J . Tetrahe-
dron Lett. 1994, 35, 5109.
2
2.4
5
2
7, 435. (d) Yamamoto, Y.; Nakamura, H. J . Med. Chem. 1993, 36,
232. (e) Yamamoto, Y.; Takamatsu, S.; Nakamura, H. J . Magn. Reson.
(12) Arylboronic ester 3a showed an optical rotation of [R]
(c ) 1.0, CHCl ). The unseparable mixture of the boronic acid 4 and
unidentified materials showed an optical rotation of [R]
0.96, CH OH). Treatment of this mixture with pinacol followed by the
esterification with benzyl bromide/Cs CO gave 3a , which showed
). This clearly indicates that no
D
+6.53
3
2
5
Ser. B 1993, 101, 198. (f) Nemoto, H.; Cai, J .; Yamamoto, Y. J . Chem.
Soc., Chem. Commun. 1994, 577. (g) Nakamura, H.; Sadayori, N.;
Sekido, M.; Yamamoto, Y. J . Chem. Soc., Chem. Commun. 1994, 2581.
D
-0.7 (c )
3
2
3
2
4.5
(
(
h) Nemoto, H.; Cai, J .; Yamamoto, Y. Tetrahedron Lett. 1996, 37, 539.
i) Nakamura, H.; Sekido, M.; Yamamoto, Y. J . Med. Chem. 1997, 40,
[R]
D
+6.65 (c ) 1.90, CHCl
3
racemization has taken place at the stage of deprotection of pinacol
and benzyl groups.
2
825.
S0022-3263(98)00818-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/19/1998

7
530 J . Org. Chem., Vol. 63, No. 21, 1998
Notes
Sch em e 2
Bis(1,3-d ip h en yl-1,3-p r op a n ed iola to)d ibor on (1b). To a
solution of tetrakis(dimethylamino)diboron (6) (3.16 g, 16.0
mmol) in THF (40 mL) was added 1,3-diphenyl-1,3-propanediol
(5) (7.30 g, 32.0 mmol) at room temperature, and the mixture
was stirred overnight at 50 °C. The solvent was removed, and
the resulting crude product was purified by recrystallization
from THF to afford 1b as a white solid (5.43 g, 72% yield): IR
-
1
1
(
KBr) 3084, 3030, 2903, 1385, 1277, 1150 cm ; H NMR (300
MHz, CDCl ) δ 7.34 (m, 20H), 5.08 (t, J ) 5.3 Hz, 4H), 2.36 (dd,
J ) 5.3, 5.3 Hz, 4H); 13C NMR (75 MHz, CDCl
) δ 141.9, 128.4,
3
3
1
4
7
27.4, 125.2, 69.8, 41.8; HRMS (EI) calcd for C30
74.2174, found m/z 474.2171. Anal. Calcd for C30
5.99; H, 5.95. Found: C, 75.96; H, 6.10.
H
H
28
O
4
B
2
m/z
: C,
28
O
4
B
2
Cbz-Tyr (Tf)-OBzl (2). To a solution of Cbz-Tyr-OBzl (2.3
g, 5.7 mmol) and 2,6-lutidine (2.7 mL, 22.6 mmol) in CH Cl (30
2
2
mL) was added triflic anhydride (1.9 mL, 11.3 mmol) at -40 °C
and the mixture was stirred for 2 h. The reaction was quenched
with water and the organic portion was extracted with ether,
washed with NaCl solution, dried over MgSO , and concentrated.
4
Purification by column chromatography on silica gel (5:1 hexane/
ethyl acetate) gave Cbz-Tyr(Tf)-OBzl (2) (2.48 g, 83% yield) as
-
1
from this diol can be easily cleaved by hydrogenolysis.13
white solid: IR (KBr) 3342, 1744, 1693, 1541, 1417, 1221 cm ;
1
H NMR (300 MHz, CDCl
J ) 8.0 Hz, 1H), 5.07 (s, 4H), 4.68 (m, 1H), 3.14 (dd, J ) 13.2,
.6 Hz, 1H), 3.05 (dd, J ) 13.2 5.6 Hz, 1H); 13C NMR (75 MHz,
CDCl ) δ 170.7, 155.4, 148.4, 136.2, 136.0, 134.7, 131.1, 128.8,
28.7, 128.7, 128.5, 128.3, 128.1, 121.2, 121.0, 67.5, 67.1, 54.6,
7.4; HRMS (EI) calcd for C25 SF m/z 537.1069, found
SF : C, 55.86; H, 4.13;
3
) δ 7.32 (s, 9H), 7.02 (s, 5H), 5.25 (d,
The reaction of the diol 5 and tetrakis(dimethylamino)-
diboron (6)14 proceeded very smoothly in THF at room
5
temperature to give bis(1,3-diphenyl-1,3-propanediolato)-
diboron (1b) in 72% yield (Scheme 2). The triflate 2
underwent the palladium-catalyzed cross-coupling reac-
tion with the diboron 1b in DMF at 100 °C, giving the
corresponding arylboronic ester 3b in 65% yield. The use
of dioxane as a solvent gave 3b in lower yield. The
protective groups of 3b were removed all at once under
3
1
3
H
22NO
22NO
7
3
m/z 537.1068. Anal. Calcd for C25
H
7
3
N, 2.61. Found: C, 55.73; H, 4.04; N, 2.75. [R]D20.9: +2.87 (c )
1.055, CHCl3).
(
S)-Ben zyl 2-((Ben zyloxyca r b on yl)a m in o)-3-[4-(((1,3-
2
the hydrogenolytic condition with Pd(OH) /C, and L-BPA
d ip h e n yl-1,3-p r op a n e d iyl)d ioxo)d iola t ob or io)p h e n yl]-
p r op a n oa te (3b). A solution of Cbz-Tyr(Tf)-OBzl (2) (1.34 g,
2.49 mmol), bis(1,3-diphenyl-1,3-propanediolato)diboron (1b)
was obtained in 74% yield without racemization.
The palladium-catalyzed cross-coupling reaction be-
tween C-OTf and B-B bonding is a key for the concise
synthesis of L-BPA from L-tyrosine. We are now in a
position to supply L-BPA, synthesized through short steps
from naturally occurring L-tyrosine, for medical and
biological research.
2
(1.30 g, 2.74 mmol), KOAc (0.73 g, 7.48 mmol), PdCl (dppf) (0.15
g, 0.20 mmol), and dppf (0.11 g, 0.20 mmol) in DMF (20 mL)
was stirred at 100 °C under argon atmosphere for 3 h. The
reaction mixture was diluted with ether, washed with NaCl
solution, dried over MgSO , and concentrated. Purification by
4
column chromatography on silica gel (6:1 hexane/ethyl acetate)
gave 3b (1.04 g, 65% yield) as a white solid: IR (KBr) 3420, 3339,
Exp er im en ta l Section
-1 1
1
703, 1497, 1456, 1312, 1290 cm ; H NMR (300 MHz, CDCl
δ 7.86 (d, J ) 7.3 Hz, 2H), 7.36 (m, 20H), 7.08 (d, J ) 7.3 Hz,
H), 5.25 (m, 1H), 5.21 (t, J ) 5.20 Hz, 2H), 5.15 (s, 2H), 5.10
(s, 2H), 4.75 (m, 1H), 3.15 (br, 2H), 2.40 (dd, J ) 5.2, 5.2 Hz,
2H); HRMS (EI) Calcd for C39 m/z 625.2636, found m/z
625.2667. Anal. Calcd for C39 : C, 74.89; H, 5.80; N,
3
)
Cbz-Tyr -OBzl. To a solution of L-tyrosine (10 g, 55 mmol)
and benzyl alcohol (25 mL) in benzene (120 mL) was added
TsOH‚H O (12.6 g, 66 mmol) at room temperature. The water
2
generated in the reaction was separated by benzene azeotropic
distillation for 2 h, and the white precipitate was filtered off.
2
H
36BNO
36BNO
6
H
6
2
1.2
The filtrate was washed with NaHCO
3
solution, dried over
2.24. Found: C, 74.92; H, 6.02; N, 2.35. [R]D : +10.13 (c )
MgSO , and concentrated. Purification by recrystallization from
ethanol gave Tyr-OBzl (11.9 g). To a solution of Tyr-OBzl (11.9
g, 44 mmol) and triethylamine (6.2 mL, 44 mmol) in methanol
4
0.235, CHCl3).
L-(4-Bor on op h en yl)a la n in e (L-BP A). To a mixture of 3b
(0.38 g, 0.59 mmol) and Pd(OH)
2 3
/C (0.10 g) in CHCl -MeOH
(
200 mL) was slowly added carbobenzoxy chloride (Cbz-Cl) (6.1
(1:1) solution was added 1 drop of AcOH under hydrogen
mL, 44 mmol) at 0 °C, and the mixture was stirred for 2 h. The
reaction was quenched with water, and the mixture was
extracted with ether, washed with NaCl solution, dried over
atmosphere, and the reaction mixture was stirred at 40 °C for
24 h. Palladium catalyst was removed by filtration through
Celite, and the solvent was evaporated. The white solid was
MgSO
4
, and concentrated. Purification by column chromatog-
raphy on silica gel (3:1 hexane/ethyl acetate) gave Cbz-Tyr-OBzl
2 2
washed with CH Cl to afford pure L-BPA (0.09 g, 74% yield):
1
(
16.5 g, 73% yield from L-tyrosine) as a white solid: IR (KBr)
H NMR (300 MHz, DCl + D O) δ 7.61 (d, J ) 7.9 Hz, 2H), 7.20
2
-
1
1
3
422, 3314, 1724, 1693, 1252, 838 cm
) δ 7.32 (m, 10H), 6.83 (d, J ) 8.5 Hz, 2H), 6.62 (d, J )
.5 Hz, 2H), 5.58 (br, 1H), 5.27 (d, J ) 8.5 Hz, 1H), 5.14 (m,
H), 5.09 (s, 2H), 4.67 (m, 1H), 3.02 (m, 2H); 13C NMR (75 MHz,
) δ 171.5, 155.8, 154.9, 136.1, 135.0, 130.4, 128.6, 128.58,
28.5, 128.5, 128.2, 128.1, 115.5, 67.3, 67.1, 55.0, 37.3; HRMS
EI) calcd for C24 m/z 405.1576, found m/z 405.1585. Anal.
Calcd for C24 23NO : C, 71.10; H, 5.72; N, 3.45. Found: C,
1.14; H, 5.76; N, 3.46.
;
H NMR (300 MHz,
(d, J ) 7.7 Hz, 2H), 4.11 (bt, J ) 6.8 Hz, 1H), 3.21 (dd, J ) 14.5,
CDCl
8
2
CDCl
1
3
21.3
5
0
.5 Hz, 1H), 3.06 (dd, J ) 14.5, 7.7 Hz, 1H); [R]
D
-8.12 (c )
5
23
.8, 1 N HCl); lit. [R]
D
-8.2 (c ) 0.7, 1 N HCl).
3
Ack n ow led gm en t . We thank Professor Norio
(
H23NO
5
Miyaura of Hokkaido University for his helpful advice
on the synthesis of the diboron compounds and their
palladium-catalyzed coupling reaction and Professor
Yuzuru Masuda of Kitami Institute of Technology for
his helpful discussions.
H
5
7
6
(
13) Malan, C.; Morin, C.; Preckher, G. Tetrahedron Lett. 1996, 37,
705.
14) Brotherton, R. J .; McCloskey, A. L.; Petterson, L. L.; Steinberg,
H. J . Am. Chem. Soc. 1960, 82, 6242.
(
J O980818R