Synthesis of Functionalised Phenylalanines Using Rhodium Catalysis in Water

Article abstract of DOI:10.1002/adsc.200390039

The efficient synthesis of substituted phenylalanine-type amino acids using a rhodium-catalysed, conjugate addition of arylboronic acids is described. The reactions are run in water and use a low loading (0.5 mol %) of rhodium catalyst.

Full text of DOI:10.1002/adsc.200390039

COMMUNICATIONS
Synthesis of Functionalised Phenylalanines Using Rhodium
Catalysis in Water
Christopher J. Chapman, Christopher G. Frost*
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
Fax: ( ‡ 44)-1225-386231, e-mail: c.g.frost@bath.ac.uk
Received: August 16, 2002; Accepted: October 19, 2002
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de or from the author.
addition of organoboronic acids to a range of activated
olefins.[9] The key steps in the catalytic cycle have
recently been elucidated and reported by Hayashi.[10]
Further to this the addition of arylboronic acids to
aldehydes,[11] imines[12] and anhydrides has also been
achieved.[13] Significant advances have also been made
by Lautens in the coupling of hetereoaromatic olefins in
aqueous media.[14] In these reactions, the catalyst
Rh2(COD)2Cl2 (COD ˆ cycloctadiene) was used with
the water-soluble ligand triphenylphosphinodisulpho-
nate (TPPDS) and sodium dodecyl sulphate (SDS) as a
phase transfer agent. For this study we investigate the
coupling of substituted arylboronic acids with amido-
Abstract: The efficient synthesis of substituted
phenylalanine-type amino acids using a rhodium-
catalysed, conjugate addition of arylboronic acids is
described. The reactions are run in water and use a
low loading (0.5 mol %) of rhodium catalyst.
Keywords: arylation; boronic acids; C-C coupling;
conjugate addition; rhodium
The synthesis of a-amino acids continues to be of acrylate electrophiles (1 4) using water as the reaction
significant interest as a consequence of the diverse utility solvent.[15]
of amino acids in chemistry and biochemistry.[1] Common
Initial experiments examined the addition of 1-
synthetic approaches include the addition to imines,[2] naphthaleneboronic acid promoted by Rh2(COD)2Cl2
carbonylation reactions[3] and catalytic hydrogenation as catalyst, selected results are shown in Table 1. It was
reactions.[4] Recently, Li has reported the conjugate clear from the outset that the presence of a free
addition of carbon nucleophiles (organotin, organobis- carboxylic acid group was having a detrimental effect
muth and organosilicon reagents) to a,b-dehydroamino
acid derivatives.[5] Here we report the utility of the boron/
rhodium transmetalation process as a means to promote
the conjugate addition of aryl nucleophiles to a,b-
B(OH)2
dehydroalanine derivatives, allowing rapid access to a
wide range of substituted phenylalanine-type a-amino
O
O
acids. Reetz has performed one example of this type of
ROOC
N
H
ROOC
N
H
Rh2(COD)2Cl2 (5 mol %)
transformation to prepare the naturally occurring amino
acid phenylalanine (Phe).[6] Synthetic analogues of Phe
provide a useful way of increasing chemical functionality
inproteinsorpeptides, andhaveconsiderablepotentialin
pharmaceutical applications. Examples of Phe-based
non-coded amino acids have been successfully utilised
in the synthesis of potent bradykinin antagonists and
oxytocin analogues.[7] Another such derivative, 4-biphe-
nylalanine is employed as an effective element in a
potent, long-acting angiotensin II antagonist.[8] This
communication details a clean, catalytic approach to
functionalised Phe derivatives.
R = H
1
Conditions
R = H
5
R = Me 2
R = Me 6
B(OH)2
O
O
ROOC
N
ROOC
N
Rh2(COD)2Cl2 (5 mol %)
Conditions
O
O
The rhodium-catalysed addition of boronic acids to
organic electrophiles has emerged as fundamental
methodology for organic synthesis. An efficient trans-
R = H
3
R = H
7
R = Et 4
R = Et 8
metalation between boron and rhodium permits the Scheme 1. Conjugate addition to dehydroalanine derivatives.
Adv. Synth. Catal. 2003, 345, No. 3
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353

Christopher J. Chapman, Christopher G. Frost
COMMUNICATIONS
Table 1. Rhodium-catalysed synthesis of amino acid derivatives.
Entry
Enamide
Conditions
Product
Yield [%][a]
1
2
3
4
1
2
3
4
4
4
H2O, 100 8C, 24 hours
H2O, 100 8C, 24 hours
H2O, 100 8C, 24 hours
H2O, 100 8C, 24 hours
H2O, SDS, 100 8C, 24 hours
H2O, 100 8C, 24 hours
5
6
7
8
8
8
< 5
30
< 5
98
89
5
6[b]
92
[a]
Isolated yield after flash chromatography.
0.5 mol % Rh2(COD)2Cl2.
[b]
Table 2. Synthesis of amino acid derivatives from 4.[a]
on the course of the reaction (Entries 1 and 3). This can
be rationalised by oxidative addition of the acid
followed by protolytic cleavage of the rhodium-aryl
bond to produce naphthalene which was the observed
major product of the reaction.[16] The utilisation of ethyl
a-phthalimidoacrylate 4 provided the addition product
in excellent isolated yield (Entry 4). The conditions
previously described by Lautens either with or without
added ligand were also effective. Remarkably, the
catalyst loading could be lowered to 0.5 mol %
Rh2(COD)2Cl2 without any loss of efficiency (Entry 6).
The increase in efficiency when using 4 compared to 2 is
due to enhanced stability of the phthalyl group in the
presence of water as well as electronic effects.
Ar
O
O
ArB(OH)2
EtOOC
N
EtOOC
N
Rh2(COD)2Cl2 (cat.)
H2O
O
O
Entry
Ar
Yield [%][b]
1
2
3
66
59
66
Under the preferred reaction conditions the scope of
the process was explored with respect tothe boronic acid
(Table 2). In all cases the reaction proceeded in good
yield to provide a useful synthetic approach to unnatural
amino acid derivatives. It was useful to note that both
electron-rich and electron-deficient arylboronic acids
could be successfully employed. Given that certain
rhodium complexes are capable of promoting the
addition of arylboronic acids to aldehydes, an interest-
ing result was that arising from the use of 4-formylbor-
onic acid (Table 2, entry 2). It appears that in aqueous
media the conjugate addition proceeds cleanly in good
yield without the need to protect the aldehyde function-
ality. The incorporation of functional groups such as
CHO, NO2 and Cl provide pharmacologically interest-
ing products and provide an opportunity for further
modification. The protecting groups can be cleaved by a
two-step route consisting of ester hydrolysis followed by
removal of the phthalyl group with hydrazine. However,
a more convenient procedure is the simultaneous
cleavage of both protecting groups under acidic con-
ditions (6 N HCl/AcOH, 4:1) which furnishes the amino
acid hydrochlorides in excellent overall yield.[17]
4
89
5
6
85
77
7
90
8
9
88
73
76
10
[a]
[b]
For typical reaction conditions, see Experimental Section.
Isolated yield after flash chromatography.
Experimental Section
In summary, the scope of the rhodium-catalysed
addition of boronic acids has been extended to allow
the efficient preparation of unnatural a-amino acid
derivatives. The reactions can be performed in water at
low catalyst loading and without added ligand. Our
efforts continue to investigate the scope of this impor-
tant carbon-carbon bond forming reaction.
General Remarks
All reactions in Table 2 were performed according to the
following procedure by using different boronic acids. Exper-
imental data for all new compounds can be found in the
supporting information.
354
Adv. Synth. Catal. 2003, 345, 353 355

Synthesis of Phenylalanines Using Rh Catalysis in Water
COMMUNICATIONS
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3-(4-Acetylphenyl)-2-(1,3-dihydro-1,3-dioxoisoindol-2-
yl)-propionic Acid Ethyl Ester (Table 2, Entry 3)
A
suspension of ethyl a-phthalimidoacrylate (61 mg,
0.25 mmol), 4-acetylbenzeneboronic acid (82 mg, 0.5 mmol),
and chloro-(1,5-cyclooctadiene)rhodium(I) dimer (6 mg,
0.0125 mmol, 5 mol %), in 3 mL of water was refluxed under
an air atmosphere. After 24 hours ethyl acetate (10 mL) was
added and the phases separated, and the aqueous phase
extracted with ethyl acetate (3 Â 10 mL). The combined
organics were washed with brine, dried over MgSO4, filtered
and concentrated under vacuum. The crude material was
purified by flash chromatography on silica gel (eluent petro-
leum ether/ethyl acetate, 4:1) to give the title compound as a
white solid; yield: 60 mg (66%); mp 131 132 8C; Rf (4:1
petroleum ether:ethyl acetate) 0.20; IR (nujol): nmax ˆ 2923,
2852, 1773, 1739, 1715, 1684, 1606, 1465, 1377, 1271, 1238, 1185,
1
1106, 1016, 954, 887, 714 cmÀ1; H NMR (300 MHz, CDCl3):
d ˆ 1.26 (3H, t, J ˆ 7.2 Hz, CH3), 2.52 (3H, s, COCH3), 3.56
3.70 (2H, m, CHCH2), 4.26 (2H, qd, J ˆ 1.9, 7.2 Hz, CH2CH3),
5.17 (1H, dd, J ˆ 6.0, 10.5 Hz, NCH), 7.28 (2H, d, J ˆ 8.3 Hz,
2,6-Ar-CH), 7.68 7.74 (2H, m, Ar), 7.76 7.82 (4H, m, Ar, 3,5-
Ar-CH); 13C NMR (75.5 MHz, CDCl3): d ˆ 197.7, 168.5, 167.4,
142.5, 135.8, 134.2, 131.5, 129.1, 128.7, 123.6, 62.2, 52.9, 34.7,
‡
‡
26.6, 14.1; MS (FAB ): [MH ]: calcd. for C21H20NO5: m/z
366.1341; found: m/z 366.1366; anal. calcd. (%) for C21H19NO5:
C 69.03, H 5.24, N 3.83; found: C 68.90, H 5.28, N 3.83.
Acknowledgements
We are grateful to Johnson-Matthey for a CASE award to CJC
and for the loan of transition metal salts. CGF thanks Astra-
Zeneca for a generous award from their strategic research fund.
[14] M. Lautens, A. Roy, K. Fukouka, K. Fagnou, B. Martin-
Matute, J. Am. Chem. Soc. 2001, 123, 5358.
References and Notes
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Adv. Synth. Catal. 2003, 345, 353 355
355