Novel synthesis of alpha-amino acids via catalysis in air and water.

Article abstract of DOI:10.1021/ol010079s

[reaction: see text] A new method was developed for the synthesis of natural and unnatural amino acid derivatives via carbon-carbon bond formation in air and water and at ambient temperature.

Full text of DOI:10.1021/ol010079s

ORGANIC
LETTERS
2001
Vol. 3, No. 13
2037-2039
Novel Synthesis of r-Amino Acids via
Catalysis in Air and Water
Tai-Sheng Huang and Chao-Jun Li*
Department of Chemistry, Tulane UniVersity, New Orleans, Louisiana 70118
cjli@tulane.edu
Received April 19, 2001
ABSTRACT
A new method was developed for the synthesis of natural and unnatural amino acid derivatives via carbon−carbon bond formation in air and
water and at ambient temperature.
Amino acids are the fundamental building blocks of peptides
and proteins that play a wide variety of roles in living
organisms and display a range of properties.1 The physi-
ological importance of R-amino acids ensures a sustained
interest in their chemistry. Classical methods for the synthesis
of R-amino acids, including displacement reactions on R-halo
acids, the Strecker synthesis, via hydantoins, and via oxazo-
lones have played key roles in the early days of amino acid
chemistry.2 Among the many recent methods developed for
the synthesis of R-amino acids are the Petasis boronic acid
method,3 the Alper double carbonylation method,4 Lewis acid
catalyzed imine additions,5 and (above all) the catalytic
hydrogenation of amino acrylates.6,7 Recently, extraordinary
progress has been made in the chemical synthesis of R-amino
acids via asymmetric catalytic hydrogenation of acet-
amidoacrylates, mostly with rhodium (as well as ruthenium,
iridium and copper) catalysts (Figure 1, route a). A large
numbers of chiral ligands have also been developed for such
a purpose.8 On the other hand, a complimentary synthesis
via carbon-carbon bond formation (Scheme 1, route b) has
Scheme 1
(1) Chemistry and Biochemistry of the Amino Acids; Barrett, G. C., Eds.;
Chapman & Hall: London 1985.
(2) Williams, R. M. In Organic Chemistry Series, Volume 7: Synthesis
of Optically ActiVe R-Amino Acids; Baldwin, J. E., Magnus, P. D., Eds.;
Pergamon Press: Oxford, 1989. Duthaler, O. R. Tetrahedron 1994, 50, 1539.
Kunz, H. In StereoselectiVe Synthesis; Helmechen, G., Hoffmann, R. W.,
Mulzer, J., Schaumann, E., Eds.; Georg Theime Verlag: Stuttgart, 1995;
Vol. E21b, p 1931; Whitesell, J. K. Acc. Chem. Res. 1985, 18, 280 and
references therein.
(3) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445.
Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798.
(4) Li, Y. S.; Alper, H. Angew. Chem., Int. Ed. 2001, 40, 779.
(5) O’Donnell, M. J.; Bennett, W. D. Tetrahedron 1988, 44, 5489.
(6) Burk, M. J. Chemtracts: Org. Chem. 1998, 11, 787.
(7) Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G. J. Chem.
Soc. A 1966, 1711.
been rarely explored. Herein, we wish to describe a novel
synthesis of R-amino acids via rhodium-catalyzed conjugated
addition of R-aminoacrylates with organotin9 and organo-
bismuth reagents under ambient conditions of air and water.
Currently, there is a wide interest in searching for
alternative media and processes for chemical and organic
synthesis.10 As a result of the natural abundance of water as
(8) For latest examples, see: Reetz, M. T.; Mehler, G. Angew. Chem.,
Int. Ed. 2000, 39, 3889. van den Berg, M.; Minnaard, A. J.; Feringa, B. L.
J. Am. Chem. Soc. 2000, 122, 11539.
10.1021/ol010079s CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/26/2001

well as the inherent advantages of using water as a solvent,
interest has been growing in studying organic reactions in
water.11 Recently, we have been exploring transition-metal-
catalyzed carbon-carbon bond formations under the quasi-
natural conditions of air and water.12 Toward such a general
goal, we recently discovered a Grignard-type phenylation
of aldehydes in water. Phenyltin derivatives (trimethyl and
tributyl) reacted effectively with aldehydes in water and
under an atmosphere of air to give nucleophilic addition
products in high yields in the presence of a catalytic amount
of rhodium catalyst.13 Subsequently, we also found that in
the presence of a rhodium catalyst, R,â-unsaturated esters
and ketones react with triphenylbismuth as well as trialkyl-
phenyl- and trialkylvinyltin reagents in aqueous media to
give the corresponding conjugated addition products under
an air atmosphere.14 While the processes are open for further
improvements, the effectiveness of such reactions led us to
explore the synthesis of amino acids under similar conditions.
Previously, the conjugated addition of acetamidoacrylates
with organocuprate reagents have been briefly studied under
inert gas atmosphere and in anhydrous solvent.15
to give the conjugated product in 72% isolated yield. No
reaction was observed without the catalyst. However, at a
low temperature (<70 °C), the bismuth compound became
a solid and only 45% of the desired product was obtained
after 2 h of sonication, which limited its reaction. When
trimethylphenyltin was used instead of the bismuth com-
pound, only 18% yield of the desired product was isolated
after refluxing overnight; most of the starting material had
decomposed. When the mixture was stirred at room tem-
perature (to prevent the decomposition), no reaction was
observed (Scheme 3). However, when the reaction mixture
Scheme 3
Electron-deficient R-phthalimidoacrylate derivatives were
chosen because of their stability in water and their enhanced
reactivity toward nucleophiles. There are a number of
methods in the literature for forming acetamidoacrylates and
related compounds.16 However, we found that the most
convenient method was via the Trost R-addition reaction of
acetylenic carboxylic derivatives catalyzed by triphenylphos-
phine in toluene.17 Thus, the reaction of ethyl propynoate
with phthalamide in toluene under Trost reaction conditions
generated the desired ethyl R-phthalimidoacrylate in 85%
yield (Scheme 2).
in water was sonicated18 at room temperature, a fast reaction
occurred to give the desired product in 82% isolated yield.
Interestingly, only 11% yield of the desired product was
obtained when the reaction mixture was sonicated in dioxane.
Various tin reagents were then examined under the same
reactions conditions of sonication in air and water (Scheme
4), and the results are listed in Table 1. Replacing trimethyltin
Scheme 2
Scheme 4
With the aminoacrylate derivative in hand, we examined
the conditions for conjugated addition. When ethyl R-phthal-
imidoacrylate was stirred with triphenylbismuth and a
catalytic amount of a Rh2(COD)2Cl2 (5 mol %) at refluxing
conditions overnight in water, a smooth reaction occurred
with tributylphenyltin (in general) decreased the yield of the
product slightly (compare entries 1 and 2, 4 and 5). Whereas
an electron-withdrawing group on the phenyl ring decreased
the yield (entries 3 and 4), no major change was observed
with electron-donating groups.
(9) Qi, S.; Moro, M.; Ono, S.; Inoue, Y. Chem. Lett. 1998, 83; Qi, S.;
Moro, M.; Inoue, Y. Chem. Commun. 1997, 1621.
(10) Caution: trimethyltin reagents are highly toxic. For general refer-
ences on green chemistry, see: Anastas, P. T.; Warner, J. C. Green
Chemistry: Theory and Practice; Oxford University Press: Oxford, 1998.
Green Chemistry: Designing Chemistry for the EnVironment; ACS
Symposium Series No. 626; Anastas, P. T., Williamson, T. C., Eds.;
American Chemical Society: Washington, DC, 1996.
(12) Li, C. J. Chem. ReV. 1993, 93, 2023. Li, C. J.; Chan, T. H.
Tetrahedron 1999, 55, 11149. Li, C. J. Tetrahedron 1996, 52, 5643.
(13) Meng, Y.; Li, C. J. J. Am. Chem. Soc. 2000, 120, 9538.
(11) Li, C. J.; Chan, T. H. Organic Reactions in Aqueous Media; John
Wiley & Sons: New York, 1997. Lubineau, A.; Auge, J.; Queneau, Y.
Synthesis 1994, 741. Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie
Academic & Professional: Glasgow, 1998.
(14) Venkatraman, S.; Li, C. J. Tetrahedron Lett. 2001, 42, 781. For
other Rh-catalyzed conjugated additions, see: Sakuma, S.; Sakai, M.; Itooka,
R.; Miyaura, N. J. Org. Chem. 2000, 65, 5951. Hayashi, T.; Senda, T.;
Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716 and references therein.
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Org. Lett., Vol. 3, No. 13, 2001

intermediate or a reductive elimination followed by hydroly-
sis of the R-tin carbonyl intermediate will result in the final
product (Scheme 5).
Table 1. Synthesis of R-Amino Acid Derivatives via
Rhodium-Catalyzed Conjugated Additions in Air and Watera
Scheme 5. Tentative Mechanism for the Rhodium-Catalyzed
Synthesis of Amino Acids
In summary, a method for the synthesis of natural and
unnatural R-amino acid derivatives was developed in air and
water. The scope (such as asymmetric synthesis), mechanism,
and synthetic applications of this reaction are currently under
investigation.19
Acknowledgment. We are grateful to the NSF (CA-
REER), the NSF-EPA joint program for a sustainable
environment, and the Louisiana Board of Regent for partial
support of our research.
Supporting Information Available: Characterization of
all products. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL010079S
(15) Cardellicchio, C.; Fiandanese, V.; Marchese, G.; Naso, F.; Ronzini,
L. Tetrahedron Lett. 1985, 26, 4387. Blanchard, P.; El Kortbi, M. S.;
Fourrey, J. L.; Robert-Gero, M. Tetrahedron Lett. 1992, 33, 3319. Bull, S.
D.; Davis, S. G.; O’Shea, M. D. J. Chem. Soc., Perkin Trans. 1 1998, 3657.
(16) Fffenberger, F.; Beissenger, T. Angew. Chem. 1982, 94, 210.
Wojciechowska, H.; Pawlowicz, R.; Andruszkiewicz, R.; Grzybowska, J.
Tetrahedron Lett. 1978, 4063. Carlstroem, A. S.; Fred, T. Synthesis 1989,
414.
(17) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119, 7595.
(18) Cintas, P.; Luche, J.-L. Green Chem. 1999, 1, 115. Synthetic Organic
Sonochemistry; Luche, J.-L., Ed.; Plenum: New York, 1998. Ganem, B.
Chemtracts: Org. Chem. 1990, 3, 438. Ley, S. V.; Low, C. M. R.
Ultrasound in Synthesis; Springer-Verlag: New York, 1989.
(19) Typical Procedure. A suspension of ethyl R-phthalimidoacrylate
(61 mg, 0.25 mmol), trimethyl(phenyl)tin (120 mg, 0.5 mmol), and chloro-
(1,5-cyclooctadiene)rhodium(I) dimer (6 mg, 0.0125 mmol) in 3 mL of water
was sonicated for 2 h in a commercial ultrasonic cleaning bath at room
temperature. After the reaction was complete (as monitored by TLC), 15
mL of ethyl acetate was added. The organic phase was separated, and the
aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined
organic layer was washed with brine (15 mL), dried over MgSO4, filtered,
and concentrated in vacuo. The crude material was purified by flash
chromatography on silica gel (eluent, hexane/ethyl acetate, 4:1) to give the
desired product (62 mg, 82%).
a All reactions were carried out at room temperature. Isolated yields are
after column chromatography on silica gel.
A tentative mechanism for the reaction involves the
insertion of rhodium in the aryl C-M bond to generate a
rhodium intermediate. The intermediate undergoes conju-
gated addition with acrylate derivatives to give a R-rhodium
carbonyl intermediate. Either direct hydrolysis of this
Org. Lett., Vol. 3, No. 13, 2001
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