Palladium-catalyzed borylation of l-tyrosine triflate derivative with pinacolborane: practical route to 4-borono-l-phenylalanine (l-BPA) derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.01.006

Efficient palladium-catalyzed borylation of protected l-tyrosine triflate with pinacolborane was achieved despite previous reports to the contrary. In addition to the use of an inexpensive boron source, the reaction was carried out in the presence of only 0.5 mol % palladium catalyst. Furthermore, the borylation can be performed using pinacolborane prepared in situ from pinacol and borane-diethylaniline complex. This represents a practical entry to 4-borono-l-phenylalanine (l-BPA) derivatives.

Full text of DOI:10.1016/j.tetlet.2010.01.006

Tetrahedron Letters 51 (2010) 1353–1355
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Tetrahedron Letters
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Palladium-catalyzed borylation of L-tyrosine triflate derivative with
pinacolborane: practical route to 4-borono-L-phenylalanine (L-BPA) derivatives
*
*
Shinya Iimura , Wenxue Wu
Chemical Development, Lexicon Pharmaceuticals, 350 Carter Road, Princeton, NJ 08540, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient palladium-catalyzed borylation of protected L-tyrosine triflate with pinacolborane was achieved
Received 15 December 2009
Revised 30 December 2009
Accepted 5 January 2010
Available online 11 January 2010
despite previous reports to the contrary. In addition to the use of an inexpensive boron source, the reac-
tion was carried out in the presence of only 0.5 mol % palladium catalyst. Furthermore, the borylation can
be performed using pinacolborane prepared in situ from pinacol and borane–diethylaniline complex. This
represents a practical entry to 4-borono-
L
-phenylalanine (
L
-BPA) derivatives.
Ó 2010 Elsevier Ltd. All rights reserved.
4-Boronophenylalanine (BPA)1 and its derivatives have at-
tracted much interest in medicinal as well as in synthetic commu-
cently reported nickel-based catalyst system was also ineffective
in this case (entry 3).12 Surprisingly, the reaction proceeded
smoothly to give the desired product 2a in good yields under stan-
dard Masuda conditions (entries 4 and 5),8 contrary to the unsuc-
cessful result reported previously under very similar conditions
(Table 1, substrate 1a). Further optimizations indicated that sol-
vent had a minor effect on the reaction, with dioxane being slightly
better than other solvents (entries 5–8). On the other hand, selec-
tion of the base was critical for the control of side product 3
(entries 5, 9–15). Tertiary amines such as triethylamine, diisopro-
pylethylamine, and N-methylmorpholine (NMM) gave excellent
results, whereas strongly coordinating bases such as DABCO and
DMAP as well as inorganic bases such as potassium acetate, potas-
sium carbonate, and cesium carbonate gave 3 as the predominant
product (entries 11–15). Though an undesired side reaction for the
borylation, the reduction could be further exploited for the deoxy-
genation of the substituted tyrosines via triflates.13
With the solvent (dioxane) and base (NMM) selected, additional
catalyst screening was performed. As the data in Table 3 indicate
that PdCl2(dppf) is a superior catalyst for this transformation (en-
tries 1–8). Although DPEphos (4) was reported to be good ligands
for borylation of halides with pinacolborane,14 it did not perform
well in this reaction (entry 7). The reaction did not proceed at all
when PdCl2 was used (entry 9), probably due to its low solubility
in the solvent system. NiCl2(dppf) was also inactive for the reaction
despite a higher catalyst loading (entry 10). It is worth noting that
PdCl2(dppf) catalyst loading can be reduced from 3 mol % to only
0.5 mol % without problems (Table 3, entries 1, 11, and 12).15 In
fact, the conversion seemed to improve slightly as the catalyst
loading was decreased from 3 mol % to 0.5 mol %. To the best of
our knowledge, this is the first example for Miyaura–Masuda bory-
lation of an aryl triflate using such a low-catalyst loading.16 The
data in Table 3 also suggest that the reaction may be sensitive to
the base/pinacolborane charges as well as their ratio. Thus, the
reaction slowed considerably when the amount of pinacolborane
nities. 10B-enriched BPA, especially the
L
isomer (
L-
10BPA),2 has
been extensively studied for the treatment of melanoma, glioma,
and other tumors in Boron Neutron Capture Therapy (BNCT).3
L-
BPA-containing peptides4 may be used as precursors to tritiated
phenylalanine-containing peptides4a or as potential biosensors.4c
Additionally, L-BPA derivatives have been extensively employed
as building blocks for the synthesis of biologically interesting mol-
ecules.5 As a result, quite a few synthetic approaches to these com-
pounds have been reported over the last two decades.5a,6 Among
the existing synthetic methods, borylation of a tyrosine triflate ap-
pears to be one of the most straightforward approaches. In fact,
borylation of a tyrosine triflate derivative using bis(pinacola-
to)diboron was reported.6f Although this borylation proceeded
smoothly under Miyaura’s conditions,7 a high catalyst loading
(8 mol %) was used. Additionally, the reagent bis(pinacolato)dibo-
ron is expensive and not atom-economical as only half of the boron
is active. To improve the efficiency of this approach, inexpensive
pinacolborane was also employed.8,9 However, this reaction ap-
peared to be rather challenging with protected tyrosine triflates
(1a, 1c, and 1d) according to the literature reports (Table 1).5a,6h
Therefore, the borylation with pinacolborane was achieved using
more expensive iodophenylalanine derivatives (1b and 1e) and a
relatively high catalyst loading (3 mol %). Encouraged by a recent
progress on transition metal-catalyzed borylation,10 we decided
to revisit this reaction using the more readily available
triflate derivatives.
L-tyrosine
We chose triflate 1a11 as the model substrate for our investiga-
tions. Initial catalyst screening results indicated that the problem
was not only the reactivity of the triflate, but also the formation
of the reduction side product 3 (Table 2, entries 1 and 2).8 A re-
* Tel.: +1 609 466 6080; fax: +1 609 466 3562 (S.I.).
E-mail address: siimura@lexpharma.com (S. Iimura).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.006

1354
S. Iimura, W. Wu / Tetrahedron Letters 51 (2010) 1353–1355
Table 1
Table 3
Previously reported borylation of tyrosine triflate derivatives with pinacolborane
Optimization for borylation of 1a with pinacolborane
O
O
Pinacolborane
O
O
Pinacolborane (2 equiv)
Catalyst
OMe
PdCl2(dppf), Et3N
O-Z
NMM (3 equiv)
OMe
NHBoc
NHBoc
O-Z
NH-Y
O
O
B
B
dioxane
NH-Y
Dioxane
80 °C, 16-24 h
80 or 100 oC
16-24 h
TfO
O
X
O
1
2
1a
2a
Yielda (%)
Substrate
X
Y
Z
Yield (%)
Ref.
Entry
Pd catalyst/ligand (mol %)
1a
1b
1c
1d
1e
OTf
I
OTf
ONf
I
Boc
Boc
Cbz
Cbz
Cbz
Me
Me
Bn
Bn
Bn
<5 (2a)
72 (2a)
Very poor (2b)
58 (2b)
5a
5a
6h
6h
6h
2a
3
1a
1
2
3
4
5
6
7
8
PdCl2(dppf) (3)
PdCl2(PCy3)2 (3)
Pd(OAc)2 (3)
Pd(OAc)2 (3)/dppf (3)
Pd(OAc)2 (3)/dppp (3)
Pd(OAc)2 (3)/dppb (3)
Pd(OAc)2 (3)/4 (3)
Pd(OAc)2 (3)/BINAP (3)
PdCl2 (3)/dppf (3)
NiCl2(dppf) (5)
88
0
2
60
42
34
34
10
0
4
0
15
9
9
10
5
7
—
83
31
49
56
61
86
100
100
6
82 (2b)
Table 2
Initial screening for borylation of 1a with pinacolborane
4
9
0
0
10
11
12
13b
14c
15b,c
0
O
PdCl2(dppf) (2)
90
95
60
4
3
3
1
O
Pinacolborane (2 equiv)
Catalyst (3 mol%)
Base (3 equiv)
OMe
NHBoc
PdCl2(dppf) (0.5)
PdCl2(dppf) (0.5)
PdCl2(dppf) (0.5)
PdCl2(dppf) (0.5)
2
36
2
OMe
NHBoc
O
B
97 (95)d,e
96 (94)d,e
Solvent
80 °C, 16-24 h
TfO
O
2
1
1a
Catalyst
2a
PPh2
O
PPh2
Entry
Base
Solvent
Yielda (%)
2a
3
1a
4
1
Pd(PPh3)4
NMM
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
i-Pr2NEt
NMM
DABCO
DMAP
KOAc
K2CO3
Cs2CO3
Dioxane
Dioxane
Toluene
Dioxane
Dioxane
ACN
5
6
4
12
—
9
6
13
13
9
8
4
73
99f
97
79
97
91
82
—
13
7
2
8
8
10
7
18
1
0
0
0
2b
3c
4d
5
Pd(OAc)2/PCy3
NiCl2(dppp)2
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
a
b
c
HPLC yield.
<5
69e
87
85
79
83
82
88
9
0
3
21
3
Pinacolborane (1.5 equiv).
NMM (1 equiv).
Isolated yield.
d
e
6
7
8
9
10
11
12
13
14
15
>99% ee.
Toluene
MeTHF
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
center. While it is unclear why the reaction was not successful in
the previous attempts,5a,6h a working mechanism improved upon
that proposed by Masuda8b can be used to explain the sensitivities
of the reaction profile to the type of bases (Scheme 1). Oxidative
addition of the active palladium (0) species to form the palladium
(II) intermediate (5) is unlikely a rate-limiting step in this reaction.
During the rate-limiting transmetalation step, either the pin-
O
OMe
NHBoc
3
O
a
b
c
d
e
f
H
B
HPLC yield.
Pd(OAc)2, 2.5 mol %; PCy3, 5 mol %.
NiCl2(dppp), 10 mol %; dppp, 10 mol %.
Pinacolborane (1.5 equiv), 100 °C.
63% isolated yield.
O
LB:
LB
H
δ+
LB+
H
98% isolated yield.
O
O
O
B
δ-
B-
L
O
L
Pd OTf
Ar
10
11
alone was reduced (entry 13), whereas it was unchanged when the
amount of NMM alone was reduced (entry 14). Moreover, the yield
was unchanged when both pinacolborane and the base amounts
were reduced (entry 15). These interesting findings suggest that
there may be some subtleties in the mechanism of borylation using
pinacolborane. Importantly, under the optimized conditions
(1.5 equiv pinacolborane), the isolated yield was 94% after chroma-
tography (entry 15).
ArOTf
5
LBH+OTf -
L
PdL2
L
Pd H
O
L
Pd B
Ar
+
L
O
Ar
6
7
The product 2a thus prepared proved to be enantiopure by chi-
ral HPLC, suggesting that no racemization occurred during the
borylation reaction. It is worth noting that a lower chiral purity
(94% ee) of 2a was reported for the reaction of the iodide substrate
1b.5a These results indicate that the present reaction conditions
can preserve the stereochemical integrity of a base-sensitive chiral
O
O
Ar
B
+
Ar H
8
9
Scheme 1. Possible working mechanism for the borylation.

S. Iimura, W. Wu / Tetrahedron Letters 51 (2010) 1353–1355
1355
Pinacol + BH3-PhNEt2
dioxane
oC to rt
O
0
O
OMe
NHBoc
Pinacolborane (2 equiv)
PdCl2(dppf) (0.5 mol%)
OMe
NHBoc
O
B
NMM
Dioxane, 80 °C
TfO
O
1a
2a
82%
Scheme 2. Borylation using pinacolborane prepared in situ.
Barnum, B. A.; Rong, F.-G.; Barth, R. F.; Codogni, I. M.; Wilson, J. G. Chem. Rev.
1998, 98, 1515; (d) Barth, R. F.; Coderre, J. A.; Vicente, M. G. H.; Blue, T. E. Clin.
Cancer Res. 2005, 11, 3987; (e) Yamamoto, T.; Nakai, K.; Matsumura, A. Cancer
Lett. 2008, 262, 143.
acolboron or the hydrogen atom can be transferred to give species
6 and 7, respectively, which upon fast reductive eliminations result
in borylation product 8 and reduction product 9, respectively. We
propose that the bases employed in this reaction may form com-
plexes 10 and 11 with pinacolborane depending on the Lewis basi-
city of the bases employed. A weakly coordinating Lewis base, such
as trialkylamines, likely forms the weakly bound complex 10
whereas a strongly coordinating Lewis base, such as DABCO and
DMAP, likely forms the strongly bound complex 11. Due to the
oxophilic nature of boron, the oxygen-centered bases possibly also
form the strongly bound complex 11. The weakly bound complex
10 activates the borylation pathway, whereas the strongly bound
‘ate’ complex 11 prefers the hydride transfer pathway.17 This
mechanism is consistent with the results summarized in Table 2.
In order to further improve the efficiency of the reaction for
large-scale manufacture, it was carried out using pinacolborane
prepared in situ (Scheme 2). The less active and more stable bor-
ane–diethylaniline complex was shown to be optimal for this pin-
acolborane preparation.18 The reaction proceeded to give 2a in 82%
isolated yield.
4. (a) Roberts, D. C.; Suda, K.; Samanen, J.; Kemp, D. S. Tetrahedron Lett. 1980, 21,
3435; (b) Samanen, J.; Cash, T.; Narindray, D.; Brandeis, E.; Yellin, T.; Regoli, D. J.
Med. Chem. 1989, 32, 1366; (c) Duggan, P. J.; Offermann, D. A. Aust. J. Chem.
2007, 60, 829.
5. For examples, see: (a) Firooznia, F.; Gude, C.; Chan, K.; Marcopulos, N.; Satoh, Y.
Tetrahedron Lett. 1999, 40, 213; (b) Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1999,
64, 2976; (c) Decicco, C. P.; Song, Y.; Evans, D. A. Org. Lett. 2001, 3, 1029; (d)
Deng, H.; Jung, J.-K.; Liu, T.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2003, 125, 9032; (e) Skaff, O.; Jolliffe, K. A.; Hutton, C. A. J. Org. Chem.
2005, 70, 7353; (f) Takahashi, K.; Nakamura, H.; Furumoto, S.; Yamamoto, K.;
Fukuda, H.; Matsumura, A.; Yamamoto, Y. Bioorg. Med. Chem. 2005, 13, 735; (g)
Combs, A. P.; Zhu, W.; Crawley, M. L.; Glass, B.; Polam, P.; Sparks, R. B.; Modi,
D.; Takvorian, A.; McLaughlin, E.; Yue, E. W.; Wasserman, Z.; Bower, M.; Wei,
M.; Rupar, M.; Ala, P. J.; Reid, B. M.; Ellis, D.; Gonneville, L.; Emm, T.; Taylor, N.;
Yeleswaram, S.; Li, Y.; Wynn, R.; Burn, T. C.; Hollis, G.; Liu, P. C. C.; Metcalf, B. J.
Med. Chem. 2006, 49, 3774; (h) Gong, Y.; Barbay, J. K.; Dyatkin, A. B.; Miskowski,
T. A.; Kimball, E. S.; Prouty, S. M.; Fisher, M. C.; Santulli, R. J.; Schneider, C. R.;
Wallace, N. H.; Ballentine, S. A.; Hageman, W. E.; Masucci, J. A.; Maryanoff, B. E.;
Damiano, B. P.; Andrade-Gordon, P.; Hlasta, D. J.; Hornby, P. J.; He, W. J. Med.
Chem. 2006, 49, 3402; (i) Nambo, M.; Noyori, R.; Itami, K. J. Am. Chem. Soc. 2007,
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Dyatkin, A. B.; Miskowski, T. A.; Hornby, P. J.; He, W. Bioorg. Med. Chem. Lett.
2008, 18, 1331.
In conclusion, an efficient borylation of a tyrosine triflate was
achieved with the use of the inexpensive pinacolborane reagent
in excellent yields and without racemization. Contrary to the pre-
vious reports, modified Masuda conditions were sufficient to
achieve satisfactory results. The catalyst loading can be reduced
to as low as 0.5 mol %. Additionally, the borylation can be carried
out using pinacolborane prepared in situ from borane–diethylani-
line complex, further reducing the cost. This work provides a prac-
tical and concise synthesis of protected 4-boronophenylalanine,
which can be either used directly as a building block in Suzuki cou-
6. (a) Samsel, E. G. U.S. Patent 5,157,149, 1992; (b) Kirihara, M.; Morimoto, T.;
Ichimoto, I. Biosci. Biotech. Biochem. 1993, 57, 1940; (c) Nakao, H.; Morimoto, T.;
Kirihara, M. Biosci. Biotech. Biochem. 1996, 60, 683; (d) Malan, C.; Morin, C.
Synlett 1996, 167; (e) Satoh, Y.; Gude, C.; Chan, K.; Firoozia, F. Tetrahedron Lett.
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1998, 63, 7529; (g) Malan, C.; Morin, C. J. Org. Chem. 1998, 63, 8019; (h)
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Zhu, W.; Ma, D. Org. Lett. 2006, 8, 261.
7. (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508; (b)
Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett. 1997, 38, 3447.
8. (a) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62, 6458; (b)
Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org. Chem. 2000, 65, 164.
9. For other examples of Pd-catalyzed borylation of aryl triflates with
pinacolborane, see: (a) Penhoat, M.; Levacher, V.; Dupas, G. J. Org. Chem.
2003, 68, 9517; (b) Brimble, M. A.; Lai, M. Y. H. Org. Biomol. Chem.
2003, 1, 2084; (c) Thompson, A. L. S.; Kabalka, G. W.; Akula, M. R.;
Huffman, J. W. Synthesis 2005, 547; (d) Altemöller, M.; Podlech, J.;
Fenske, D. Eur. J. Org. Chem. 2006, 1678; (e) Tam, V. K.; Liu, Q.; Tor, Y.
Chem. Commun. 2006, 2684; (f) Ahmed, V.; Liu, Y.; Silvestro, C.; Taylor,
S. D. Bioorg. Med. Chem. 2006, 14, 8564.
pling reactions or converted to L
-BPA using known procedures.6g
Acknowledgment
The authors are grateful to Lexicon’s analytical chemistry group
for their assistance in HPLC and LC–MS.
10. For a recent review, see: Ishiyama, T.; Miyaura, N. Chem. Rec. 2004, 3, 271.
11. Triflate 1a was prepared according to a literature procedure: Shieh, W.-C.;
Carlson, J. A. J. Org. Chem. 1992, 57, 379.
Supplementary data
12. Rosen, B. M.; Huang, C.; Percec, V. Org. Lett. 2008, 10, 2597.
13. For the latest deoxygenation methods of phenols, see: (a) Sajiki, H.; Mori, A.;
Mizusaki, T.; Ikawa, T.; Maegawa, T.; Hirota, K. Org. Lett. 2006, 8, 987; (b) Mori,
A.; Mizusaki, T.; Ikawa, T.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Tetrahedron
2007, 63, 1270.
14. Broutin, P.-E.; Cerna, I.; Campaniello, M.; Leroux, F.; Colobert, F. Org. Lett. 2004,
6, 4419.
15. Further reduction in catalyst charge to 0.3 mol % afforded unsatisfactory
yields.
General methods, typical borylation procedure, preparative pro-
cedure of 1a, copies of 1H and 13C NMR spectra of compounds 1a,
2a, and 3, and chiral HPLC chromatograms for 2a are available.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.01.006.
16. Recently, a Miyaura–Masuda borylation of aryl halides using low catalyst
loading was reported, see: Billingsley, K. L.; Buchwald, S. L. J. Org. Chem. 2008,
73, 5589.
17. Indeed, metal borohydride is known to reduce halides and sulfonates in the
presence of a palladium catalyst. See: (a) Egli, R. A. Helv. Chim. Acta 1968, 51,
2090; (b) Hutchins, R. O.; Learn, K. J. Org. Chem. 1982, 47, 4380.
18. (a) Tucker, C. E.; Davidson, J.; Knochel, P. J. Org. Chem. 1992, 57, 3482; (b)
Kikuchi, T.; Nobuta, Y.; Umeda, J.; Yamamoto, Y.; Ishiyama, T.; Miyaura, N.
Tetrahedron 2008, 64, 4967. and references therein.
References and notes
1. Snyder, H. R.; Reedy, A. J.; Lennarz, W. J. J. Am. Chem. Soc. 1958, 80, 835.
2. For preparation of 10B-enriched
L-BPA, see: Hattori, Y.; Asano, T.; Kirihata, M.;
Yamaguchi, Y.; Wakamiya, T. Tetrahedron Lett. 2008, 49, 4977. and references
therein.
3. For reviews, see: (a) Hawthorn, M. F. Angew. Chem., Int. Ed. Engl. 1993, 32, 950;
(b) Morin, C. Tetrahedron 1994, 50, 12521; (c) Soloway, A. H.; Tjarks, W.;