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C O M M U N I C A T I O N S
Table 1. pH-Dependent Synthesis of R-Amino Acids with Nonpolar
(Type A, Entries 1-8), Uncharged Polar (Type B, Entries 9 and 10),
and Charged Polar (Type C, Entries 11 and 12) Substituents by
Reductive Amination of R-Keto Acids with HCOONH4 or with NH3
and HCOOY (Y ) Na or H) in the Presence of 1(PF6) or 2(SO4) in
Water at 80 °C for 6 ha,b
Scheme 1
R-hydroxy
amine and
hydride ion
donors
carboxylic
acid
R-amino acid
optimum
pH
c
entry complex
symbol TOF yield (%)d yield (%)d
1
2
3
4
5
6
7
8
9
1(PF6) HCOONH4
2(SO4) HCOONH4
2(SO4) NH3/HCOOH
2(SO4) 15NH3/DCOONa
2(SO4) HCOONH4
2(SO4) HCOONH4
2(SO4) HCOONH4
2(SO4) HCOONH4
2(SO4) HCOONH4
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
6.5
6.5
Ala
Ala
Ala
Ala
Val
Leu
Ile
Phe
Tyr
Tyr
Glu
Glu
185
94
6
4
4
4
3
7
5
8
6
228 96 (94)e
211
249
121
157
113
249
96
96
97
93
95
92
176 94 (85)e
153 91
170 78 (70)e
167 81
10 2(SO4) 15NH3/DCOONa
11 2(SO4) HCOONH4
7
19
15
12 2(SO4) 15NH3/DCOONa
a 1(PF6) or 2(SO4)/R-keto acid/HCOONH4 ) 1 (0.8 µmol)/200 (0.16
mmol)/4000 (3.2 mmol). b 2(SO4)/R-keto acid/5% aqueous NH3/HCOOY
(Y ) Na or H) ) 1 (0.8 µmol)/200 (0.16 mmol)/4000 (3.2 mmol)/4000
(3.2 mmol). c Turnover frequency: {mol of R-amino acids/mol of 2(SO4)}/
(initial 1 h). d For 6 h (based on R-keto acids). e Isolated yield for 6 h.
of R-hydroxy carboxylic acids has been made possible by using
acid-stable hydride complexes under the optimized pH conditions
in water.
(O in Figure 2) are obtained exclusively above pH 5 by the catalytic
reductive amination of R-keto acids with 15NH3, DCOO-, and
2(SO4) in H2O (but not in D2O) (eq 4).
Acknowledgment. Financial support of this research by the
Ministry of Education, Science, Sports, and Culture, Japan, Society
for the Promotion of Science, and Grants-in-Aid for Scientific
Research (11228205, 15036242, and 15350033) is greatly acknowl-
edged.
References
Table 1 shows the results of the reductive amination of R-keto
acids with HCOONH4 (entries 1, 2, 5, 6, 7, 8, 9, and 11), 5% NH3/
H2O and HCOOH (entry 3), or 5% 15NH3/D2O and DCOONa
(entries 4, 10, and 12) in the presence of 1(PF6) (entry 1) or 2(SO4)-
(entries 2-12) in water at 80 °C at the optimized pH (5.0-6.5).
The product yields determined by 1H NMR of R-amino acids with
type A, B, and C substituents are 92-97%, 91-94%, and 78-
81%, respectively. It was confirmed that no reaction occurred in
the absence of the catalysts, hydride ion donors, or amine donors
(as blank experiments). Moreover, large-scale synthesis of the
R-amino acids has been made possible.12
(1) Beller, M.; Eckert, M. Angew. Chem., Int. Ed. 2000, 39, 1010-1027.
(2) McMurry, J. Organic Chemistry; Brooks/Cole: Pacific Cove, CA, 2000;
pp 1084-1085.
(3) (a) Yoneda, F.; Kuroda, K. J. Chem. Soc., Chem. Commun. 1982, 927-
929. (b) Kitamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura, M.
J. Org. Chem. 2002, 67, 8685-8687. (c) Kadyrov, R.; Riermeier, T. H.;
Dingerdissen, U.; Tararov, V. I.; Bo¨rner, A. J. Org. Chem. 2003, 68,
4067-4070.
(4) Stoichiometric synthesis of R-amino acids by reductive amination: (a)
Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93,
2897-2904. (b) Shinkai, S.; Hamada, H.; Dohyama, A.; Manabe, O.
Tetrahedron Lett. 1980, 21, 1661-1664. (c) Shi, G.; Cao, Z.; Zhang, X.
J. Org. Chem. 1995, 60, 6608-6611. (d) Nakamura, K.; Ohno, A.; Oka,
S. Tetrahedron Lett. 1977, 18, 4593-4594.
(5) Catalytic synthesis of amines by reductive amination: (a) Tararov, V. I.;
Kadyrov, R.; Riermeier, T. H.; Bo¨rner A. Chem. Commun. 2000, 1867-
1868. (b) Gross, T.; Seayad, A. M.; Ahmad, M.; Beller, M. Org. Lett.
2002, 4, 2055-2058. (c) Kadyrov, R.; Riermeier, T. H. Angew. Chem.,
Int. Ed. 2003, 42, 5472-5474.
The pH-dependent reductive amination of R-keto acids with NH3
and HCOO- catalyzed by the iridium complexes is proposed in
Scheme 1. The reaction is started by acid-catalyzed nucleophilic
attack of NH3 to the carbonyl carbon of R-keto acids to produce
intermediary R-imino acids, followed by subsequent reduction of
the CdN bond in the R-imino acids by 1. Protonation of the
carbonyl oxygen of R-keto acids makes carbonyl carbon more
susceptible to the nucleophilic addition. Under acidic conditions,
(6) Abura, T.; Ogo, S.; Watanabe, Y.; Fukuzumi, S. J. Am. Chem. Soc. 2003,
125, 4149-4154.
(7) HCOONH4 acts as an amine source as well as a hydride ion source.
(8) Voet, D.; Voet, J. G.; Pratt, C. W. Fundamentals of Biochemistry; John
Wiley & Sons: New York, 1999; pp 79-84.
(9) The formation of H2 was confirmed by GC analysis.
(10) The pKa value of HCOOH is 3.6 at 25 °C.
(11) Turnover frequencies {TOFs ) (mol of R-amino acids/mol of 1(PF6) or
2(SO4)/(initial 1 h)) were determined by 1H NMR.
+
NH3 also undergoes protonation to form NH4 that cannot act as
(12) For example, 10 g scale synthesis of tyrosine: 95% isolated yield.
Conditions: 2(SO4)/R-keto acid/HCOONH4 ) 1(277.5 µmol)/200 (55.5
mmol)/4000 (1.11 mol), 80 °C, 24 h.
the amine donor, when only transfer hydrogenation of R-keto acids
takes place to afford R-hydroxy carboxylic acids. Thus, the highly
chemoselective synthesis of R-amino acids with negligible formation
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J. AM. CHEM. SOC. VOL. 126, NO. 10, 2004 3021