Functionalization of aromatic amino acids via direct C-H activation: Generation of versatile building blocks for accessing novel peptide space

Article abstract of DOI:10.1021/ol1015674

Functionalized α-amino acid building blocks have been prepared in good yield with high regiocontrol and preservation of stereochemistry via iridium-catalyzed borylation of suitably protected aromatic α-amino acid derivatives. The utility of these systems

Full text of DOI:10.1021/ol1015674

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3870-3873
Functionalization of Aromatic Amino
Acids via Direct C-H Activation:
Generation of Versatile Building Blocks
for Accessing Novel Peptide Space
Falco-Magnus Meyer,† Spiros Liras,‡ Angel Guzman-Perez,‡ Christian Perreault,‡
Jianwei Bian,‡ and Keith James*,†
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, and CVMED Chemistry, Pfizer Inc.,
445 Eastern Point Road, Groton, Connecticut 06340
kjames@scripps.edu
Received July 7, 2010
ABSTRACT
Functionalized r-amino acid building blocks have been prepared in good yield with high regiocontrol and preservation of stereochemistry via
iridium-catalyzed borylation of suitably protected aromatic r-amino acid derivatives. The utility of these systems in peptide couplings and
Suzuki reactions has been demonstrated.
The plethora of natural products and therapeutic agents which
incorporate natural and non-natural R-amino acids provides
continued impetus to the search for efficient new methods
to construct these fragments with full control of stereochem-
istry.1 Strategies for novel R-amino acid synthesis encompass
resolution of racemic amino acids,2 modification of readily
available homochiral R-amino acids,3 and de novo construc-
tion of R-amino acids with creation of the key R-stereocenter
via asymmetric induction.4 Methods which involve the
modification of existing R-amino acids are particularly
attractive, since the key R-stereocenter is already installed
and synthetic routes can be very short.5 However, they
require mild reaction conditions and compatibility with
sensitive functionality.
As part of a program to discover novel peptides for
potential therapeutic use, we envisaged the incorporation of
functionalized R-amino acids (bearing a concealed reactive
center) into an intact peptide chain as an efficient means of
introducing functional diversity (through organometallic
† The Scripps Research Institute.
‡ Pfizer Inc.
(1) (a) Bhat, S. V.; Nagasampagi, B. A.; Sivakumar, M. Chemistry of
Natural Products; Springer: New York, 2005; 317-393. (b) Wang, L.;
Shultz, P. G. Angew. Chem., Int. Ed. 2005, 44, 34–66.
(2) For recent examples and reviews see: (a) Choi, Y. K.; Kim, Y.; Han,
K.; Park, J.; Kim, M.-J. J. Org. Chem. 2009, 74, 9543–9545. (b) Ahn, Y.;
Ko, S.-B.; Kim, M.-J.; Park, J. Coord. Chem. ReV. 2008, 252, 647–658. (c)
Mart´ın-Matute, B.; Ba¨ckvall, J. E. Curr. Opin. Chem. Biol. 2007, 11, 226–
232. (d) Kim, M.-J.; Ahn, Y.; Park, J. Bull. Korean Chem. Soc. 2005, 26,
515–522. (e) Pa`mies, O.; Ba¨ckvall, J. E. Chem. ReV. 2003, 103, 3247–
3261.
(4) For recent examples and reviews see: (a) Zhang, H.; Syed, S.; Barbas,
C. F. Org. Lett. 2010, 12, 708–711. (b) Zuend, S. J.; Coughlin, M. P.;
Lalonde, M. P.; Jacobsen, E. N. Nature 2009, 461, 968–971. (c) Banphavichit,
V.; Mansawat, W.; Bhanthumnavin, W.; Vilaivan, T. Tetrahedron 2009,
65, 5849–5854. (d) Connon, S. J. Angew. Chem., Int. Ed. 2008, 47, 1176–
1178. (e) Na´jera, C.; Sansano, J. M. Chem. ReV. 2007, 107, 4584–4671. (f)
Hashimoto, T.; Maruoka, K. Chem. ReV. 2007, 107, 5656–5682. (g)
O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506. (h) Lygo, B.; Andrews,
B. I. Acc. Chem. Res. 2004, 37, 518–525.
(3) (a) Ross, A. J.; Lang, H. L.; Jackson, R. F. W. J. Org. Chem. 2010,
75, 245–248. (b) Jackson, R. F. W.; James, K.; Wythes, M.; Wood, A.
J. Chem. Soc., Chem. Commun. 1989, 644–5.
(5) Rilatt, I.; Caggiano, L.; Jackson, R. F. W. Synlett 2005, 18, 2701–
2719.
10.1021/ol1015674  2010 American Chemical Society
Published on Web 08/09/2010

coupling reactions) at a late stage in a synthetic sequence.
In view of their stability and synthetic versatility, we were
especially drawn to the incorporation of R-amino acids
featuring an aryl boronate ester. Aryl boronic acids and esters
have had an enormous impact on modern drug synthesis,
potentially allowing access to a wide range of aryl, heteroaryl,
vinyl, alkynyl, and acyl derivatives, and providing compat-
ibility with peptide-based substrates.6
reactions,7c the products were predominantly or exclusively
the 3,5-disubstituted derivatives.
The unsubstituted phenyalanine derivative 1 yielded a statisti-
cal mixture of 3- and 4-isomers (2a and 2b respectively), as
well as diborylated material (2c, structure not shown), in high
overall yield (Table 1). In contrast, the bromo, trifluoromethyl,
methoxy, methyl, and chloro substituents were all sufficiently
large to direct the reaction to exclusively one regioisomer, in
very good to excellent yield (Table 1, 4a, 6a, 12a, 14a, and
16a). Notably, the fluoro-substrate 9 yielded a similar product
ratio to the unsubstituted system, reflecting the commonly held
view that a fluoro substituent offers effectively the same steric
hindrance as a hydrogen atom (Table 1, 10a and 10b). This
finding is consistent with the obeservations of other workers.10
A very small amount of 3,4-isomer could also be detected in
the reaction of the 3-cyano derivative, reflecting the slightly
smaller size of this substituent compared to, for example, a
methyl group (Table 1, 8a and 8b).10 These borylated phenylal-
anine derivatives were stable, readily isolated, and purified by
column and/or preparative thin layer chromatography. Further-
more, preparation of the chloro derivative (Table 1, 16a) could
be run at multigram scale, with improved yields. The enan-
tiopurity of a representative example, the m-trifluoromethyl
derivative (Table 1, 6a), was confirmed by chiral HPLC analysis
of starting material and product (generated at 90 °C in this case),
demonstrating that both were >98% ee.
To implement this strategy, we envisaged that the neces-
sary boronate derivatives could be generated by use of the
emerging repertoire of C-H activation methodologies,
applied directly on readily available R-amino acid systems.
In particular, we were drawn to the pioneering work of
Hartwig and Miyaura,7 Smith and Maleczka,8 and others
using iridium-catalyzed aryl borylations, in the hope that it
would enable the required functionalization under conditions
compatible with typical amino acid protecting group strate-
gies and preservation of stereochemical integrity.
We report now the realization of this approach and
describe the efficient construction of a series of m-aryl-
boronate-substituted R-amino acid derivatives, generated via
direct iridium-catalyzed borylation of protected, commer-
cially available R-amino acids, together with examples of
their incorporation and reactivity within simple peptides.
During the course of our studies, the first report of such a
transformation on a protected amino acid derivative ap-
peared.9
As a control experiment, to confirm that regiochemical
outcome was determined by steric effects, the 2-chlorophe-
nylalanine derivative 17 was subjected to the standard
reaction conditions. As expected, both 2,4- and 2,5-deriva-
tives (18a and 18b, respectively) were isolated as a 46:54
mixture in 86% combined yield (Scheme 1a). In addition,
given the lack of regiocontrol observed with the 3-fluoro
A series of readily available meta-substituted N-Boc-
phenylalanine methyl esters (prepared in one protection
step from commercially available materials) were treated
with bis(pinacolato)diboron (B2pin2) together with cata-
lytic [Ir(OCH3)COD)]2 and 4,4′-di-tert-butyl-2,2′-bipyridine
(dtbpy) to yield the corresponding borylated derivatives
(Table 1). As expected, given the importance of steric effects
on the regiochemistry of iridium-catalyzed borylation
Scheme 1. Further Examples of Iridium-Catalyzed Borylation of
Amino Acid Derivatives
Table 1. Examples of Iridium-Catalyzed Borylation of
Substituted Phenylalanine Derivatesa
X
3,5-isomer [%]
3,4-isomer [%]
yield [%]
H (1)
Br (3)
60 (2a)
19 (2b)
ND
ND
<5 (8b)
34 (10b)
ND
81b
80c
84
>98 (4a)
>98 (6a)
>95 (8a)
66 (10a)
>98 (12a)
>98 (14a)
>98 (16a)
CF3 (5)
CN (7)
F (9)
OCH3 (11)
CH3 (13)
Cl (15)
91
91
84d
77c
73c
ND
ND
a All reactions were performed at 0.5 mmol scale in 2.5 mL of hexanes
at 60 °C with 1.2 equiv of B2pin2 in a sealed tube. Isomer ratio determined
by H NMR. b Yield includes 21% diborylated material (2c). c Conducted
1
at 90 °C with 1.5 equiv of B2pin2. d (R)-Isomer used.
Org. Lett., Vol. 12, No. 17, 2010
3871

derivative, the 4-fluoro derivative 19 was examined and
yielded a 67:33 mixture of 3,4-monoborylated and 3,4,5-
diborylated products (20a and 20b, respectively), again
illustrating the lack of steric control offered by the fluorine
substituent (Scheme 1b).
Given the excellent yield and regiocontrol achieved with
meta-substituted phenylalanine derivatives, we also explored
a series of protected heteroarylalanine derivatives (Table 2).
temperature, using only 0.5 equiv of B2pin2, a good yield of
crude product, could be obtained, but as a result of protode-
borylation on chromatography, only a 25% yield of the 3,5-
substituted material 26 was finally isolated (Table 2). Both
these thienyl substrates appeared significantly more reactive
than their phenyl counterparts. In contrast, the reaction with
the 3-pyridylalanine derivative 27 was sluggish, requiring
elevated temperatures in order to achieve full conversion of
the starting material. However, the reaction yielded a single
3,5-substituted product 28 (X ) Bpin) in moderate yield
(Table 2). Since this boronate ester was found to be unstable
toward chromatographic purification, the reported yield
corresponds to a two-step sequence including Suzuki-
Miyaura coupling with p-nitroiodobenzene to yield 28 (X
) p-nitrophenyl).
Table 2. Examples of Iridium-Catalyzed Borylation of
Heteroaryl Amino Acid Derivatives
Tryptophan derivatives represent attractive substrates for
this functionalization paradigm, given the abundance of
tryptophan in biologically active peptides and the multiple
possible positions open to iridium-catalyzed C-H activation,
depending upon the protection regime employed. Thus, as
recently reported,11 the unsubstituted N-Boc-tryptophan
methyl ester 29 yielded predominantly the 2-substituted
product 30a, in moderate yield (Table 2, entry 4). In contrast,
the tryptophan derived tricyclic amino acid 21, in which the
2-position is substituted, yielded predominantly the 7-boryl-
ated product 22 (Scheme 1c).12 To again confirm the
stereochemical integrity of the products in this series, chiral
HPLC analysis of the 2-borylated product 30a (Table 2) was
undertaken, confirming that the enantiomeric excess was
>98%.
As a means of demonstrating the synthetic utility of these
amino acid boronic esters, representative examples have been
subjected to peptide coupling and Suzuki-Miyaura reactions
in order to access biaryl and heterobiaryl amino acids typical
of those used as components of biologically active molecules.
Thus, in a “one-pot” process, N-Boc-2-thienylalanine methyl
ester 23 (Table 2) could be selectively borylated and then
treated directly, after removal of solvent, with methyl
3-iodobenzoate, under standard Suzuki-Miyaira reaction
conditions, to yield the heterobiaryl-amino acid derivative
31 in 81% overall yield (Scheme 2a). This heterobiaryl motif
is featured in recently claimed endothelin convertase inhibi-
tors13 and Factor IX/XI inhibitors,14 and also represents a
a Reaction conducted at 25 °C with 0.5 equiv of B2pin2. b Reaction
conducted at 80 °C overnight with [Ir(OMe)(COD)]2 (3 mol %), dtbpy (6
mol %), and B2pin2 (0.9 equiv). Borylated product 28 (X ) Bpin) unstable;
yield based upon Suzuki coupling with p-nitroiodobenzene to yield product
28 (X ) p-nitrophenyl). c Reaction conducted in a microwave reactor in
MTBE with [Ir(OMe)(COD)]2 (1.5 mol %), dtbpy (3 mol %), and B2pin2
(0.7 equiv). Isolated as a 6:1 mixture of 2-borylated 30a to 2,7-diborylated
30b material (structure not shown).
N-Boc-2-thienylphenylalanine methyl ester 23 yielded
exclusively the 5-borylated product 24 in excellent yield
(Table 2). In contrast, the 3-thienyl derivative 25 yielded a
mixture of 3,5-monoborylated and 2,3,5-diborylated products,
as a result of reaction at both positions adjacent to sulfur in
this system. With careful control of reaction time and
(8) (a) Tse, M. K.; Cho, J.-Y.; Smith, M. R. Org. Lett. 2001, 18, 2831–
2833. (b) Chotana, G. A.; Rak, M. A.; Smith, M. R. J. Am. Chem. Soc.
2005, 127, 10539–10544. (c) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle,
R. C.; Maleczka, R. E., Jr.; Smith, M. R., III. J. Am. Chem. Soc. 2006,
128, 15552–15553.
(9) Kallepalli, V. A.; Shi, F.; Sulagna, P.; Onyeozili, E. N.; Maleczka,
R. E.; Smith, M. R. J. Org. Chem. 2009, 74, 9199–9201.
(10) Hurst, T. E.; Macklin, T. K.; Becker, M.; Hartmann, E.; Ku¨gel,
W.; Parisienne-La Salle, J.-C.; Batsanov, A. S.; Marder, T. B.; Snieckus,
V. Chem.sEur. J. 2010, 16, 8155–8161.
(6) (a) Miyaura, N. Synlett 2009, 13, 2039–2050. (b) Miyaura, N. Bull.
Chem. Soc. Jpn. 2008, 81, 1535–1553. (c) Martin, R.; Buchwald, S. L.
Acc. Chem. Res. 2008, 41, 1461–1473. (d) Bellina, F.; Carpita, A.; Rossi,
R. Synthesis 2004, 15, 2419–2440. (e) Chalker, J. M.; Wood, C. S. C.;
Davis, B. G. J. Am. Chem. Soc. 2009, 131, 16346–16347.
(11) The procedure reported in ref 9 yielded material with an optical
rotation of similar magnitude but opposite sign to what we observed. In
correspondence with the authors, we have confirmed that our data are
correct.
(7) (a) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390–391. (b) Takagi, J.; Sato,
K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N. Tetrahedron Lett. 2002, 5649–
5651. (c) Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N. Chem.
Commun. 2003, 2924–2925. (d) Ishiyama, T.; Takagi, J.; Yonekawa, Y.;
Hartwig, J. F.; Miyaura, N. AdV. Synth. Catal 2003, 345, 1103–1106.
(12) Small amounts of other borylated material were observed in the
crude product but could not be characterized.
(13) Fink, C. A.; Firoozina, F. WO Patent 55723, 1999.
3872
Org. Lett., Vol. 12, No. 17, 2010

modification, for example, further Suzuki-Miyaura cou-
plings via the chlorine substituent, under more vigorous
conditions, to yield trisubstituted systems, or hydrogenolytic
removal of the chlorine atom (which would then have served
as a regiochemical directing group).
Scheme 2. Examples of Novel Amino Acid and Peptide
Synthesis with Borylated Amino Acids
In conclusion, we have developed an efficient synthesis
of borylated aryl- and heteroaryl-amino acids, and explored
the scope of this procedure with regard to regioselectivity
and preservation of stereochemistry. We have applied this
methodology in the construction of a novel set of usefully
functionalized, homochiral amino acids, and confirmed their
compatibility with both standard peptide coupling conditions
and Suzuki-Miyaura coupling reactions. Furthermore, we
have demonstrated their utility in the generation of other
novel amino acid and peptide derivatives which feature
functional groups commonly encountered in biologically
active molecules. These meta-functionalized systems comple-
ment the more readily available para-substituted phenylala-
nine derivatives, accessible via, for example, the triflate of
tyrosine.16 Future synthetic studies will further explore the
scope of reactivity of these borylated amino acids and their
deployment in the construction of a broader range of
biologically active peptides.
novel protected analogue of a recently published AMPA-
kainate agonist.15
Acknowledgment. This work was supported by Pfizer
Worldwide R&D. The authors would like to thank David
Price, Rob Maguire, Alan Mathiowetz, and Jeffrey Elleraas
of Pfizer Worldwide R&D for helpful discussions and
support.
Further, the borylated amino acid 16a derived from N-Boc-
3-chlorophenylalanine methyl ester (Table 1) could be
hydrolyzed and coupled smoothly to (S)-alanine methyl ester
to yield a borylated dipeptide. This could be reacted directly
under Suzuki-Miyaura conditions with 5-bromopyrimidine
to furnish the novel, protected heterobiaryl-substituted dipep-
tide 12 in 44% overall yield for the three steps (Scheme 2b).
While an interesting structure in itself, this chloro-substituted
system also offers the possibility of further chemoselective
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Mjalli, A. M. M.; Gohimmukkula, D. R.; Tyagi, S. U.S. Patent
124654, 2009.
OL1015674
(15) Szyman˜ska, E.; Pickering, D. S.; Nielsen, B.; Johansen, T. N.
Bioorg. Med. Chem. 2009, 17, 6390–6401.
(16) Iimura, S.; Wu, W. Tetrahedron Lett. 2010, 51, 1353–1355.
Org. Lett., Vol. 12, No. 17, 2010
3873