Synthesis of unnatural amino acid derivatives via palladium-catalyzed 1,4-addition of boronic acids

Article abstract of DOI:10.1016/j.tetlet.2010.03.034

Aryl and alkenyl amino acid derivatives were synthesized by a palladium-catalyzed 1,4-addition of the corresponding boronic acids to 2-acetamidoacrylate.

Full text of DOI:10.1016/j.tetlet.2010.03.034

Tetrahedron Letters 51 (2010) 2655–2656
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Tetrahedron Letters
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Synthesis of unnatural amino acid derivatives via palladium-catalyzed
1,4-addition of boronic acids
*
Devalina Ray, Abijah M. Nyong, Amarnath Natarajan
Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Aryl and alkenyl amino acid derivatives were synthesized by a palladium-catalyzed 1,4-addition of the
corresponding boronic acids to 2-acetamidoacrylate.
Received 12 February 2010
Revised 5 March 2010
Accepted 9 March 2010
Available online 15 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Our laboratory is interested in developing small molecule inhib-
itors of protein-protein interactions. Recent studies showed that
the tetrapeptide pSPTF binds the carboxy terminus domains of
the early onset breast cancer gene 1 (BRCT-BRCA1) with micromo-
lar affinities.1 Structural studies show that the phenylalanine
residue (F) in pSPTF makes a key hydrophobic contact with the
BRCT-BRCA1.2 To explore this hydrophobic pocket we planned to
generate unnatural amino acids with various aryl side chains.
Metal-catalyzed 1,4-addition of organometallic reagents to ace-
tamidoacrylates is an effective strategy to access unnatural amino
acids, and rhodium has been the metal of choice to carry out this
transformation.3 Recently a palladium-phosphite system was suc-
cessfully used in the 1,4-addition of arylboronic acids to generate
3-arylpropanoic acid derivatives.4 The phosphite in the palla-
dium-catalyzed 1,4-addition suppressed the typically observed
Mizoroki–Heck type of oxidative coupling product.
lyzed 1,4-addition conditions failed to produce either the desired
products or the side products. Therefore, we carried out a survey
Table 1
Optimization of the palladium-phosphite-catalyzed 1,4-addition of arylboronic acid
to methyl-2-acetamidoacrylate
We speculated that palladium-phosphite-catalyzed 1,4-addi-
tion of aryl boronic acid to 2-acetamidoacrylate could provide a di-
rect route to aryl and alkenyl side chain-containing unnatural
amino acids. In this Letter, we report the synthesis of various aryl
and alkenyl amino acid derivatives generated by a palladium-phos-
phite-catalyzed 1,4-addition of the corresponding boronic acids to
acetamidoacrylate. Our studies show that palladium (low cost op-
tion) can serve as a viable alternative to rhodium for the synthesis
of unnatural amino acids from acetamidoacrylates.
Entrya
Base
Solvent
% Isolated yield
In the previously reported palladium-phosphite-catalyzed 1,4-
addition of arylboronic acids to eneones, the formation of the
desired product and two side products, namely, biaryl formed
due to the oxidative homocoupling, and the Mizoroki–Heck
product was reported.4b Our initial attempts to add a rather bulky
boronic acid (10-bromoanthrace-9-ylboronic acid) to methyl-2-
acetamidoacrylate using the reported palladium-phosphite-cata-
3
4
5
1
2
3
NaOAc
CsF
DMF
DMF
DMF
DMF
0
15
30
13
13
25
12
9
20
0
0
0
40
0
10
0
0
25
50
59
0
59
0
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
4
5b
6
DMF
DMSO
Toluene
THF
7
8
9
52
0
12
30
DCM
a
Reaction conditions: Pd(OAc)2 (0.06 mmol), P(OPh)3 (0.05 mmol), 1 (1.3 mmol),
and 2 (1.0 mmol).
* Corresponding author. Tel.: +1 402 559 3793; fax: +1 402 559 8270.
E-mail address: anatarajan@unmc.edu (A. Natarajan).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.034

2656
D. Ray et al. / Tetrahedron Letters 51 (2010) 2655–2656
leads to two possible intermediates A and B that are probably in
equillibrium.5 The desired product is generated when the palla-
dium enolate A is quenched while the b-hydride elimination of B
will yield the Mizoroki–Heck product. The presence of excess ace-
tate (either by the addition of sodium acetate or by the use of stoi-
chiometric amounts of palladium acetate) drives the equilibrium
toward B resulting in the formation of the unsaturated product 5.
We extended this methodology (Table 1, entry 4) to generate a
set of unnatural amino acids (summarized in Table 2).6a We ob-
tained the desired products in modest yields (50–60%) and in most
cases isolated the oxidatively homocoupled biaryl as the side prod-
uct. Compounds 3a–d and 3f are known, while compounds 3e and
3g are new unnatural amino acids.6
Scheme 1. Plausible mechanism.
In summary, we report a palladium-phosphite-catalyzed 1,4-
addition of aryl or alkenyl boronic acids to generate unnatural ami-
no acids. We are currently exploring the use of chiral phosphites in
this reaction which will be reported in due course.
of bases and solvents to identify the optimal conditions for the
reaction (summarized in Table 1).
Unlike the addition to enones, we found that the use of carbon-
ates (Table 1, entry 3 and 4) as the base yielded the highest
amounts of the desired product, while the use of sodium acetate
(Table 1, entry 1) resulted in the formation of the oxidative Mizor-
oki–Heck product. We also found that the use of polar aprotic sol-
vents resulted in higher yields of the desired product when
compared to non-polar solvents. Additionally, under catalytic con-
ditions the reaction did not reach completion, and with stoichiom-
etric amount of Pd(OAc)2 the major product isolated was the
Mizoraki–Heck product (Table 1, entry 4 vs entry 5). A plausible
mechanistic pathway for this observation shown in Scheme 1 is
identical to that of the corresponding addition to enones.4 The
insertion of the arylpalladium species into the acetamidoacrylate
Acknowledgment
This work was supported by NIH R01CA127239.
References and notes
1. Lokesh, G. L.; Muralidhara, B. K.; Negi, S. S.; Natarajan, A. J. Am. Chem. Soc. 2007,
129, 10658–10659.
2. (a) Campbell, S. J.; Edwards, R. A.; Glover, J. N. M. Structure 2010, 18, 167–176;
(b) Joseph, P. R. B.; Yuan, Z.; Kumar, E. A.; Lokesh, G. L.; Kizhake, S.; Rajarathnam,
K.; Natarajan, A. Biochem. Biophys. Res. Commun. 2010. doi:10.1016/
j.bbrc.2010.01.098.
3. (a) Cardellicchio, C.; Fiandanese, V.; Marchese, G.; Naso, F.; Ronzini, L.
Tetrahedron Lett. 1985, 26, 4387–4390; (b) Reetz, M. T.; Moulin, D.; Gosberg,
A. Org. Lett. 2001, 3, 4083–4085; (c) Chapman, C. J.; Wadsworth, K. J.; Frost, C. J. J.
Organomet. Chem. 2003, 680, 206–211; (d) Navarre, L.; Darses, S.; Genet, J. P.
Angew. Chem., Int. Ed. 2004, 43, 719–723; (e) Navarre, L.; Martinez, R.; Genet, J.
P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159–6169.
Table 2
4. For review: (a) Gutnov, A. Eur. J. Org. Chem. 2008, 4547–4554; (b) Horiguchi, H.;
Tsurugi, H.; Satoh, T.; Miura, M. J. Org. Chem. 2008, 73, 1590–1592.
5. Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816–5817.
6. (a) The general reaction conditions were as follows: arylboronic acids (1) (1.3 mmol),
methyl-2-acetamido acrylate (2) (1 mmol), Pd(OAc)2 (0.059 mmol), P(OPh)3
(0.05 mmol), and Cs2CO3 (1.66 mmol) were added to DMF (4 mL) and heated to
75 °C. The reaction mixture was maintained at that temperature until completion
of the reaction was detected by TLC (3–5 h). The reaction was then quenched with
water (5 mL) and the reaction mixture was extracted with ethyl acetate
(10 mL ꢀ 3). The organic layer was washed with brine (10 mL), dried over
sodium sulfate, and evaporated. The resulting crude product was purified by
column chromatography using a hexane/ethyl acetate solvent system.
Methyl 2-acetamido-3-(10-bromoanthracen-9-yl)propanoate (3): 1H NMR
(500 MHz, CDCl3): d 1.97 (s, 3H), 3.21 (s, 3H), 4.0 (dd, 1H, J = 14.5, 9 Hz), 4.24
(dd, 1H, J = 14.5, 5.5 Hz), 5.0 (m, 1H), 6.23 (d, NH), 7.60 (m, 4H) 8.62 (d, 4H,
J = 10 Hz). 13C NMR (125 MHz, CDCl3): d 23.1, 30.9, 52.3, 53.3, 123.6, 124.3, 126.4,
126.8, 128.8, 128.9, 130.2, 131.3, 169.8, 172.3. MS(APCI+): 400.2 (M+H).
(E)-Methyl-2-acetamido-5-phenylpent-4-enoate (3e): 1H NMR (400 MHz, CDCl3): d
1.94 (s, 3H), 2.56–2.71 (m, 2H), 3.68 (s, 3H), 4.66–4.72 (m, 1H), 5.92-6.00 (m, 1H),
6.10 (d, br NH), 6.38 (d, 1H, J = 15.62 Hz) 7.14–7.28 (m, 5H). 13C NMR (100 MHz,
CDCl3): d 0.9, 23.1, 35.7, 51.9, 52.4, 123.4, 126.1, 127.6, 128.5, 134.0, 136.7, 169.7,
172.3. MS(APCI+): 248.2 (M+H).
Synthesis of unnatural amino acids via the palladium-phosphite-catalyzed 1,4-
addition of arylboronic acid to methyl-2-acetamidoacrylate
Entry
Ar
% Yield
3
4
a
50
12
b
51
52
0
0
(1E, 3E)-1,4-diphenylbuta-1,3-diene (4e): 1H NMR (400 MHz, CDCl3): d 6.68–6.74
(m, 4H), 6.96-7.03 (m, 4H), 7.25–7.28 (m, 4H), 7.37 (t, 8H, J = 7.33 Hz), 7.47 (d, 8H,
J = 7.33 Hz). 13C NMR (100 MHz, CDCl3): d 126.3, 127.5, 128.6, 129.2, 132.8, 137.3.
Methylacetylamino-(4-phenoxymethyl-phenyl)-acetate (3g): 1H NMR (400 MHz,
CD3OD): d 1.80 (s, 3H), 2.74–2.80 (dd, 1H, J = 13.67, 8.79 Hz), 2.92–2.98 (dd, 1H,
J = 14.16, 8.30 Hz), 3.56 (s, 3H), 4.49 (dd, 1H, J = 8.79, 5.86 Hz), 4.93 (s, 2H), 6.80 (d,
2H, J = 8.79 Hz), 7.00 (d, 2H, J = 8.79 Hz), 7.19 (t, 1H, J = 7.33 Hz), 7.25 (t, 2H,
J = 7.33 Hz), 7.31 (d, 2H, J = 7.33 Hz). 13C NMR (100 MHz, CD3OD): d 21.0, 36.5,
51.5, 54.4, 69.8, 114.7, 127.4, 127.7, 128.3, 129.2, 130.0, 137.6, 158.0, 171.9, 172.5.
MS(APCI+): 328.2 (M+H).
c
d
e
49
59
9
8
4,40-Bis-phenoxymethyl-biphenyl (4g): 1H NMR (400 MHz, CDCl3): d 5.00 (s, 4H),
6.75 (d, 4H, J = 6.8 Hz), 6.85 (d, 4H, J = 6.8 Hz), 7.32–7.43 (m, 10H). 13C NMR
(100 MHz, CDCl3): d 70.9, 116.2, 116.2, 127.7, 128.1, 128.8, 128.9, 137.4, 149.8,
153.2.
(b) Youn, I. K.; Yon, G. H.; Pak, C. S. Tetrahedron Lett. 1986, 27, 2409–2410; (c)
Karim, A.; Mortreux, A.; Petit, F.; Buono, G.; Peiffer, G.; Siv, C. J.
Organomet.Chem.1986, 317, 93–104. (d) Kurihara, K.; Yamamoto, Y.; Miyaura, N.
Tetrahedron Lett. 2009, 50, 3158.
f
56
60
9
g
11