A concise preparation of 4-borono-l-phenylalanine (L-BPA) from L-phenylalanine

Full text of DOI:10.1021/jo980295n

J . Org. Chem. 1998, 63, 8019-8020
8019
Notes
A Con cise P r ep a r a tion of
-Bor on o-L-p h en yla la n in e (L-BP A) fr om
L-P h en yla la n in e
an (unstable) L-serine-derived organozinc with a bor-
onated aromatic partner was used as the key reaction
4
(
disconnection a). We felt, however, that introduction of
a boronic acid moiety in a phenylalanine derivative
disconnection b) would yield a conceptually simple and
(
Christophe Malan and Christophe Morin*
potentially more straightforward approach to 1. We now
Laboratoire d'Etudes Dynamiques et Structurales de la
S e´ lectivit e´ , UMR CNRS 5616, Universit e´ de Grenoble,
report on such a conversion, which is based on the cross
coupling of pinacoldiboronates with aromatic deriva-
3
8402 Saint Martin d'H e` res, France
12,13
tives,
as well as on the availability of 4-iodo L-
1
4
phenylalanine 2 which can be prepared by electrophilic
Received February 18, 1998
iodination of L-phenylalanine.
1
5,16
4
-Boronophenylalanine, a tyrosine analogue in which
Tetrakis(dimethylamino)diboron (3)
reacted with
dl-1,3-diphenyl-1,3-propanediol17 to give diboronate 4
the hydroxyl group is replaced by a dihydroboryl group,
1
was the first member to be described of the increasingly
(72%), in which the boronates are protected by reducible
important family of boronated analogues of biomolecules.2
18
groups. Reaction of 4 with the iodophenylalanine de-
The L enantiomer (L-BPA, 1) has been shown to ac-
cumulate preferentially in melanomic cells, which has
rivatives 5 or 6, under the conditions developed for such
palladium(0)-catalyzed couplings, provided the desired
3
-5
12
3
led to its use in the treatment of malignant melanoma
products, however, in low conversion. As large amounts
of 1,3-diphenyl-1,3-propanediol were also isolated, the use
of a more base-stable boronic acid protecting group
seemed indicated and led us to consider Miyaura’s
reagent (bis-pinacolato diboronate, 7).19 In the presence
6
,7
through Boron Neutron Capture Therapy.
Until re-
8
cently, 1 was prepared by resolution, the racemic mate-
rial being prepared in four steps from p-bromotoluene.1
Two enantioselective syntheses of 1 based on asymmetric
hydrogenation of a dehydroamino acid derivative have
then appeared9 as well as a synthesis which has taken
,10
advantage of the chiral pool.11 In the latter, coupling of
(
1) Snyder H. R.; Reedy, A. J .; Lennarz, W. M. J . J . Am. Chem. Soc.
1
958, 80, 835.
(
(
2) For a review, see: Morin, C. Tetrahedron 1994, 50, 12521.
3) Mishima, Y.; Honda, C.; Ichihashi, M.; Obara, H.; Hiratsuka,
of 7, 6 gave the desired coupling product 8, which could
be isolated in 88% yield. However, protection of the
carboxylic acid of the phenylalanine partner was not
necessary, provided an extra equivalent of base was used,
and thus the reaction could be performed directly with
5
. Although the isolated yield of the coupled product 9
is somewhat reduced (65%), the synthesis is shortened.
Simultaneous deprotection of both the amine and boronic
following: Barth, R. F.; Soloway, A. H.; Fairchild, R. G. Sci. Am. 1990,
2
1
63, 68. Hatanaka, H. Borax Rev. 1991, 9, 5. Slatkin, D. N. Brain 1991,
14, 1609. Morris, J . H. Chem. Br. 1991 331. Hawthorne, M. F. Angew.
(12) Ishiyama, T.; Murata, M.; Miyaura, N. J . Org. Chem. 1995, 60,
7508. Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett.
1997, 38, 3447.
(13) Giroux, A.; Han, Y.; Prasit, P. Tetrahedron Lett. 1997, 38, 3841.
(14) Lei, H.; Stoakes, M. S.; Herath, K. P. B.; Lee, J .; Schwabacher,
A. W. J . Org. Chem. 1994, 59, 4206.
(15) Urry, G.; Wartik, T.; Moore, R. E.; Schlesinger, H. I. J . Am.
Chem. Soc. 1954, 76, 5293.
(16) N o¨ th, H.; Fritz, P.; Meister, W. Angew. Chem. 1961, 73, 762.
N o¨ th, H.; Fritz, P. Z. Anorg. Allg. Chem. 1963, 322, 297.
(17) Depr e` s, J .-P.; Morat, C. J . Chem. Educ. 1992, 69, A232.
(18) Malan, C.; Morin, C.; Preckher, G. Tetrahedron Lett. 1996, 37,
6705.
Chem. 1993, 105, 997 (Int. Ed. Engl. 1993, 32, 950). Barth, R. F.;
Soloway, A. H.; Brugger, R. M. Cancer Invest. 1996, 14, 534. Beddoe,
A. H. Br. J . Radiol. 1997, 70, 665. Soloway, A. H.; Tjarks, W.; Barnum,
B. A.; Rong, R.-A., Barth, R. F.; Codogni, I. M.; Wilson, J . G. Chem.
Rev. 1998, 98, 1515.
(
7) Flam, F. Science 1994, 265, 1799. Law, A. Science 1995, 267,
56.
8) Roberts, D. C.; Suda, K.; Samanen, J .; Kemp. D. S. Tetrahedron
Lett. 1980, 21, 3435.
9
(
(
9) Samsel, E. G. US Patent 5157149.
(10) Nakao, H.; Morimoto, T.; Kirihata, M. Biosci. Biotech. Biochem.
1
996, 60, 683.
11) Malan, C.; Morin, C. Synlett 1996, 167.
(19) Bis(pinacolato)diboron is commercially available from Lan-
caster.
(
1
0.1021/jo980295n CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/03/1998

8
020 J . Org. Chem., Vol. 63, No. 22, 1998
Notes
138 °C (lit.22 138 °C), whose spectroscopic properties matched
those of ref 22 and were identical with an authentic sample
kindly provided by N. Miyaura.
acid protecting groups of 9 could then be effected with
boron tribromide (79%) to give pure 1. Subsequently, it
was found that deprotection could be carried out on the
unpurified intermediate 9, as L-BPA can be easily crys-
tallyzed from the crude reaction mixture at its isoelec-
tronic point (pH ) 6.2).The overall yield of 1, identical
with an independently prepared sample,11 from 5 is then
N-(ter t-Bu t yloxyca r bon yl)-4-iod o-L-p h en yla la n in e (5).
To a stirred suspension of 4-iodo-L-phenylalanine 2 (2.44 g, 8.38
mmol) in 1 M aqueous sodium hydroxide (9.25 mL) was added
tert-butyl alcohol (6.5 mL). Melted (30 °C) di-tert-butyl dicar-
bonate (2 mL, 8.71 mmol) was then added dropwise in 3 min,
and the mixture was stirred for 15 h. Water (10 mL) was then
added to the clear solution, which was followed by extraction
with n-pentane. The organic layer was washed with saturated
aqueous sodium hydrogenocarbonate, the combined aqueous
layers were cooled at 4 °C, and the pH was adjusted to ca. 1.5
with a 1 M aqueous potassium hydrogenosulfate solution and
extracted 4 × 10 mL) with diethyl ether. The organic layers
were pooled, dried (sodium sulfate), and evaporated. The clear
oil was then taken up in n-hexane to afford white crystals of 5
5
3%.
2
3
22
1
(
)
2.77 g, 84%): mp 85-6 °C (n-hexane), lit. 120-121 °C. [R]
D
+21.2 (c 1.2, AcOEt). lit.23 [R]
22
) +21.3 (c 1.2, AcOEt). H
D
NMR (200 MHz) δ 1.2 (s 9 H), 2.7 (m, 1 H), 2.85 (m, 1 H), 4.15
m, 1 H), 5.2 (d, J ) 7.5 Hz), 6.75 and 7.3 (2 × 2H, AA′XX′
(
system, J app ) 8 Hz). 13C NMR (50 MHz) δ 27.8, 36.0, 55.4, 78.3,
9
2.2, 130.0, 132.1, 155.2, 168.1.
-Bor on o-L-p h en yla la n in e (1). Under argon a solution of
(610 mg, 2.4 mmol), 1,1′-bis(diphenylphosphino)ferrocene
4
7
dichloropalladium (complex with dichloromethane) (52 mg, 0.064
mmol), potassium acetate (825 mg, 8.41 mmol), and N-tert-Boc-
4
-iodo-L-Phe 5 (820 mg, 2.1 mmol) in dry dimethyl sulfoxide (25
Thus, a practical, four-step synthesis of L-BPA (>97%
mL) was stirred at 80 °C for 24 h. After cooling to room
temperature, it was diluted with ethyl acetate (150 mL) and
washed with 1 M aqueous hydrochloric acid and then water (3
× 20 mL). The aqueous layers were extracted with ethyl acetate
ee)20 has been developed from L-phenylalanine that
proceeds in 22% overall yield and requires no chromato-
graphic purification. The overall transformation consists
of a facile replacement of the para-hydrogen of L-Phe by
a dihydroxyboryl group and should be open to extrapola-
tion for the preparation of other 4-substituted L-phenyl-
alanine derivatives through Suzuki-type couplings, as
noted before11 and recently achieved.
(
3 × 20 mL), and the combined organic layers were dried (sodium
sulfate). For analytical purposes a sample of N-(ter t-bu tyloxy-
ca r bon yl)-4-p in a cola tobor on o-L-p h en yla la n in e could be ob-
tained at this stage by column chromatography on silica gel
22
(CH
2
Cl2/CH
3
OH 97.5/2.5). 9: oil: [R]
D
2 2
) +22.5 (c 1.4, CH Cl );
21
IR (NaCl) 3434, 3334, 2971, 1710, 1610,1391, 1354 cm -1
NMR (200 MHz) δ 1.2 (s, 9 H), 1.3 (s 12 H), 3.1 (m, 2 H), 4.55
m, 1 H), 5.1 (d, J ) 7.5 Hz, 1 H), 7.1 and 7.7 (2 × 2H, AA′XX′
1
; H
(
Exp er im en ta l Section
13
system, J app ) 8 Hz). C NMR (50 MHz) δ 24.7, 28.2, 37.8, 53.3,
1
1
8
3
0.0, 83.7, 128.4, 134.9, 139.3, 155.3, 176.0. B NMR (96.3 MHz)
Gen er a l Meth od s. Dry DMSO was stored under Ar on 4 Å
molecular sieves, and benzene was distilled over Na before use.
After workup, the volatiles were evaporated under reduced
pressure without heating. Standard abrevations are used for
NMR description of spectra which were recorded on Brucker
apparatus at the field indicated; the residual absorption of the
+
1.5 (large s); MS (EI) m/z 346 (1): (M - COOH) , 274 (24): (M
+
+
- NHBoc - H)
, 217 (100): (M - CH(COOH)NHBoc) . Anal.
Calcd for C20H30BNO6: C 61.40, H 7.73. Found: C 61.78, H 7.89.
The preceding crude oil, obtained after evaporation of the
volatiles, was dissolved in dry dichloromethane (12 mL) and
stirred at -78 °C under argon. Boron tribromide (3.4 mL, 36
mmol) was then added in 2-3 min, and the green reaction
mixture was stirred at -78 °C for 2 h before removing the cooling
bath; stirring was continued for 20 h before setting again at -78
°C. Methanol (8 mL) was then added dropwise (CAUTION), and
after warming to room temperature the mixture was filtered on
Celite; the cake was rinsed with methanol (5 × 2 mL) and water
(2 mL) added to the filtrate which was then concentrated to ca.
2 mL. The pH was set to 6.2 with 4 M aqueous potassium
carbonate, and 1 (233 mg, 53%) crystallized on standing at 4
3
NMR solvent (CDCl ) was taken as the internal reference except
1
1
for B NMR spectra for which BF
reference.
3 2
/Et O was used as an external
Bis(p in a cola to)d ibor on (7). Under argon, to a stirred
solution of tetrakis(dimethylamino)diboron 3 (3.45 g, 17.43
mmol) in dry benzene (40 mL) was added via syringe in 30 min
a solution of 2,3-dimethylbutane-2,3-diol (4.12 g, 34.86 mmol, 2
equiv) in dry benzene (45 mL). After stirring for 1 h, a solution
of hydrogen chloride in diethyl ether (35 mL of a 1 M solution,
1
1
23
3
5 mmol) was added dropwise via syringe in 30 min and the
°C: mp 285-290 °C, lit. 285-290 °C, [R]
0.1 M HCl), lit. [R]
data were identical to those of a sample prepared according to
ref 11.
D
) -8.0° (c ) 1.2;
8
23
mixture stirred for 20 h. The white precipitate was filtered off
and rinsed with dry benzene (3 × 5 mL); the filtrate was
evaporated under reduced pressure, and the residue was taken
up in n-pentane (150 mL) and filtered and the cake washed
several times with dry n-pentane. The filtrate was washed with
water (3 × 40 mL), dried (sodium sulfate), and evaporated to
dryness; the pentane extraction and washing procedure was
repeated three times to then give pure 7 (4.06 g - 92%), mp
D
) -8.2° (c ) 0.7; 0.1 N HCl); the spectral
Ack n ow led gm en t. Dr. N. Miyaura, Hokkaido Uni-
versity, is thanked for providing a sample of bis-
(
pinacolato)diboron, as well as for details of its large
scale preparation. C. Malan gratefully thanks the Ligue
Nationale contre le Cancer for financial support.
(
20) This value was obtained by comparison of the observed optical
rotation with the literature (see Experimental Section).
21) A protected imidazolidinone derivative of L-BPA has thus been
J O980295N
(
(22) N o¨ th, H.; Z. Naturforsch. 1984, 39b, 1463.
(23) Brundish, D. E.; Wade, R. J . Chem. Soc., Perkin Trans. 1 1976,
2186.
prepared; see: Satoh, Y.; Gude, C.; Chan, K.; Firooznia, F. Tetrahedron
Lett. 1997, 38, 7645.