Palladium-catalyzed synthesis of phosphine-containing amino acids

Full text of DOI:10.1021/jo960077z

2922
J . Org. Chem. 1996, 61, 2922-2923
Sch em e 1
P a lla d iu m -Ca ta lyzed Syn th esis of
P h osp h in e-Con ta in in g Am in o Acid s
Scott R. Gilbertson* and Gale W. Starkey
Department of Chemistry, Washington University,
Campus Box 1134, St. Louis, Missouri 63130-4899
known,15 one should be able to convert the OH of tyrosine
to a phosphine by proceeding through the aryl triflate.
Recently, a group from Merck Process Research has
reported this transformation using nickel catalysis.16 Cai
et al. have developed a practical method for the conver-
sion of dinaphthol to BINAP without racemization of the
sensitive starting diphenol.
Received J anuary 12, 1996 (Revised Manuscript Received
February 22, 1996)
The use of phosphine ligands in organometallic chem-
istry is ubiquitous.1,2 Phosphine metal complexes have
been used in applications from catalysis3-7 to chelation
of metals for medical imaging.8-11 For some time we have
been interested in the synthesis of new chiral phosphines
based on the utilization of biological structures. As a
consequence, we are attempting to develop new routes
to highly functionalized phosphines. One of the severe
limitations on the chemistry of phosphine ligands is the
difficulty of their synthesis. Most phosphines are syn-
thesized by either addition of a Grignard or organo-
lithium reagent to a phosphine chloride or reaction of
phosphide anion with an electrophile.12,13 Both of these
routes are incompatible with sensitive functionality,
particularly base-sensitive groups. The phosphide anion
is often sufficiently nucleophilic to react with typical
organic protecting groups, particularlly ethers and esters.
To facilitate the synthesis of phosphines containing
complicated functionality, especially protected amino
acids, we have developed a catalytic method for the
conversion of phenols to arylphosphines (Scheme 1). To
demonstrate the utility of this reaction, we have used this
chemistry to convert derivatives of tyrosine to phos-
phines. This chemistry has also been used to convert the
phenolic hydroxyl of a tyrosine-containing peptide to a
phosphine group.
In 1987, Stille reported the palladium-catalyzed reac-
tion of aryl halides with (trimethylstannyl)diphenylphos-
phine and (trimethylsilyl)diphenylphosphine.14 The Stille
coupling provides a mild method for the formation of a
wide variety of arylphosphines. As part of a larger
project, in which we are interested in synthesizing
peptides that contain phosphines in their side chains, a
transformation that appealed to us was conversion of the
OH of tyrosine to a phosphine. We felt that given the
Stille precedent, along with the fact that palladium-
catalyzed couplings with aryl and vinyl triflates are well
Independent of the Merck group, we have developed a
palladium-catalyzed version of the reaction. Conversion
of the protected amino acids to their triflates was
performed by the method of McMurry and Scott.17-19
Reaction with N-phenyltrifluoromethanesulfonamide and
diisopropylethylamine gives good to excellent yields of
the required aryl triflates (Table 1). Stille’s procedure
to convert aryl halides to phosphines uses (trimethyl-
stannyl)diphenylphosphine as the source of phosphine.
Our attempts to use this reagent under palladium
catalysis with aryl triflates resulted in no reaction. We
found that readily available diphenylphosphine is an
acceptable source of phosphorus for our reaction. Ini-
tially, it was found that N-acyltyrosine could be converted
to its triflate. Reaction of the triflate with diphenylphos-
phine and Pd(OAc)2 in the presence of dppb gave the
phosphine amino acid in good yield, albeit with racem-
ization of the R-carbon. As expected, racemization of the
amino acid R-carbon is sensitive to the protecting group
on the amine. Replacement of the acetate with t-Boc
allows the reaction to be run without racemization. As
an example, reaction of diphenylphosphine and the
triflate of N-tBoc-L-tyrosine benzyl ester with palladium
under our conditions gave a good yield of the correspond-
ing phosphine, without racemization at the R carbon
(Table 1, entry 2).20 This reaction also proceeds with the
ortho and meta isomers of tyrosine, as well as with
hydroxylphenylglycine to give new phosphine ligands
(Table 1).
There appear to be distinct differences between this
system and the Merck method. The Merck group re-
ported that the use of palladium under their conditions
gave no reaction. One explanation for the difference in
reactivity is the use of DMSO as the solvent in our
system. It is not known if the effect of DMSO is intrinsic
to the solvent or simply due to the ability of run the
reaction at a higher temperature in DMSO. We also
found the reaction does not take place in DMF with
palladium. The potential issue of oxidation of the metal
species in the catalytic cycle by DMSO does not appear
to be a problem.21,22 In our hands, the Nickel system
(1) Collman, J . P.; Hegedus, L. S.; Norton, J . R.; Finke, R. G.
Principles and Applications of Organotransition Metal Chemistry;
University Science Books: Mill Valley, CA, 1987.
(2) Tolman, C. A. Chem. Rev. 1977, 77, 313.
(3) Ojima, I. Catalytic Asymmetric Synthesis; VCH: New York, 1993.
(4) Ojima, I.; Clos, N.; Bastos, C. Tetrahedron 1989, 45, 6901.
(5) Noyori, R.; Kitamura, M. Enantioselective Catalysis with Metal
Complexes an Overview; Springer Verlag: New York, 1989; Vol. 5.
(6) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49.
(7) Stille, J . K.; Su, H.; Brechot, P.; Parrinello, G.; Hegedus, L. S.
Organometallics 1991, 10, 1183.
(8) Katti, K. V.; Volkert, W. A.; Ketring, A. R.; Singh, P. R. US Patent
No. WO 93/08839, 1993.
(9) Abrams, M. J .; Larsen, S. K.; Shaikh, S. N.; Zubieta, J . Inorg.
Chim. Acta 1991, 185, 7.
(10) Deutsch, E.; Libson, K.; Becker, C. B.; Francis, M. D.; Tofe, A.
J .; Ferguson, D. L.; McCreary, L. D. J . Nucl. Med. 1980, 21, 859.
(11) Deutsch, E.; Libson, K. Comments Inorg. Chem. 1984, 3, 83.
(12) Organophosphorous Chemistry; The Royal Chemical Society:
London, 1969-1983; Vols. 1-15.
(13) Kosolapoff, G. M.; Maier, L., Eds. Organic Phosphorus Com-
pounds, 2nd ed.; Wiley-Interscience: New York, 1972; Vol. 1.
(14) Tunney, S. E.; Stille, J . K. J . Org. Chem. 1987, 52, 748.
(15) Scott, W. J .; Crisp, G. T.; Stille, J . K. J . Am. Chem. Soc. 1984,
106, 4630.
(16) Cai, D.; Payack, J . F.; Bender, D. R.; Hyghes, D. L.; Verhoeven,
T. R.; Reider, P. J . J . Org. Chem. 1994, 59, 7180.
(17) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1983, 24, 979.
(18) Scott, W. J .; McMurry, J . E. Acc. Chem. Res. 1988, 21, 47.
(19) Petrakis, K. S.; Nagabhushan, T. L. J . Am. Chem. Soc. 1987,
109, 2831.
(20) The optical purity of the amino acid was determined by coupling
to optically active alanine and determining the ratio of diastereomers.
(21) Semmelhack, M. F.; Helquist, P. M.; J ones, L. D.; Keller, L.;
Mendelson, L.; Ryono, L. S.; Smith, J . G.; Stauffer, R. D. J . Am. Chem.
Soc. 1981, 103.
S0022-3263(96)00077-1 CCC: $12.00 © 1996 American Chemical Society

Communications
Ta ble 1. Syn th esis of Am in o Acid Tr ifla tes a n d
J . Org. Chem., Vol. 61, No. 9, 1996 2923
Sch em e 2
P h osp h in e Liga n d s
phosphine oxides. We attempted the phosphine sulfide
analog of the Morgans reaction. If successful, this
method would have provided the phosphine sulfides
directly from the aryl triflates. We found the sulfur
analog of the reaction developed by Morgans yielded only
recovered starting material. This is likely due to poison-
ing of the catalytic metal by the phosphine sulfide.
While this reaction is a convenient route to phosphine
derivatives of tyrosine it also presents the possibility for
the direct conversion of tyrosine residues in larger
peptides to phosphine ligands. To demonstrate the
feasability of this idea we have run the reaction on
tyrosine-containing pentapeptide 21. Pentapeptide 21
was treated with N-phenyltrifluoromethanesulfonamide
and diisopropylethylamine. Reaction of the purified
triflate under the standard reaction conditions discussed
above gave the phosphine-containing peptide 22, in 78%
yield (Scheme 2). This reaction indicates that it may be
possible to use this chemistry to convert the phenols of
naturally occuring tyrosine-containing proteins to phos-
phines.
results in cleavage of the acid protecting group along with
formation of the phosphine product.
The phosphine amino acids were reacted with elemen-
tal sulfur to convert the potentially air-sensitive phos-
phine group to a phosphine sulfide group, which is stable
to chromatography in air. We have shown previously
that the sulfide group is an effective protecting group for
phosphines, being easily removed with Raney nickel.23,24
In conclusion, this reaction can be used to convert
derivatives of tyrosine and hydroxyphenylglycine to
phosphine ligands as the single amino acids or when they
are present in larger peptides. We are currently using
this chemistry to synthesize phosphine ligands for use
in catalysis and in the development of metal binding
groups for medical imaging.
Morgans et al. have reported the reaction of aryl
triflates with a variety of phosphorus species under
palladium catalysis. They found reaction with diphen-
ylphosphine oxide gives a product similar to the phos-
phine sulfides we ultimately obtain. There is an impor-
tant functional difference between these two types of
products. The conversion of phosphine oxides to phos-
phines is not a facile reaction. It is generally performed
with silanes or hydride reducing agents. We have never
been able to perform this conversion on amino acid based
Ack n ow led gm en t. We gratefully acknowledge the
Washington University High-Resolution NMR Facility,
partially supported by NIH 1S10R02004, and the Wash-
ington University Mass Spectrometry Resource Center,
partially supported by NIHRR00954, for their as-
sistance. G.W.S. thanks Monsanto for support in the
form of a graduate fellowship.
(22) Semmelhack, M. F.; Helquist, P. M.; J ones, L. D. J . Am. Chem.
Soc. 1971, 93, 5908.
(23) Gilbertson, S. R.; Chen, G.; McLoughlin, M. J . Am. Chem. Soc.
1994, 116, 4481.
(24) A detailed example of the Raney nickel reduction of a phosphine
sulfide to a phosphine is included in the supporting information.
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental and spectroscopic data for all described compounds (10
pages).
J O960077Z