One-pot synthesis of α-amino acids from CO2 using a bismetal reagent with Si-B bond

Article abstract of DOI:10.1021/ol302952r

In the presence of 1.1 equiv of PhMe₂Si-Bpin, 5 equiv of CsF, and 20 mol % of TsOH·H₂O, precursors of N-Boc-imines can be converted into the corresponding α-aryl or α-alkenyl glycine derivatives under gaseous CO₂ in moderate-to-high yields with a single operation. α-Isobutenyl glycine thus obtained can be further derivatized into various types of α-amino acids including N-Boc-leucine, serine, and glycine derivatives in short steps.

Full text of DOI:10.1021/ol302952r

ORGANIC
LETTERS
2012
Vol. 14, No. 24
6202–6205
One-Pot Synthesis of r‑Amino Acids
from CO2 Using a Bismetal Reagent with
SiꢀB Bond
Tsuyoshi Mita,* Jianyang Chen, Masumi Sugawara, and Yoshihiro Sato*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
tmita@pharm.hokudai.ac.jp; biyo@pharm.hokudai.ac.jp
Received October 26, 2012
ABSTRACT
In the presence of 1.1 equiv of PhMe2Si-Bpin, 5 equiv of CsF, and 20 mol % of TsOH H2O, precursors of N-Boc-imines can be converted into the
3
corresponding R-aryl or R-alkenyl glycine derivatives under gaseous CO2 in moderate-to-high yields with a single operation. R-Isobutenyl glycine thus
obtained can be further derivatized into various types of R-amino acids including N-Boc-leucine, serine, and glycine derivatives in short steps.
R-Amino acids are core molecules exhibiting various
functions in bio- and organic chemistry. It is well-known
that R-amino acids are critical to life as building blocks of
peptides, proteins, and many natural products. Therefore,
many practical methods have been developed for the
synthesis of chiral/racemic amino acids.1 However, amino
acid synthesis through R-carboxylation of amine deriva-
tives with CO2 was only achieved by using a strongly basic
reagent such as BuLi at a very low temperature.1g As part
of our ongoing research program aimed at utilization of
CO2 gas, a ubiquitous, inexpensive, and sustainable C1
feedstock, for organic synthesis,2 we are interested in the
synthesis of R-amino acids through CO2 incorporation by
a mild and convenient way. In 2011, we reported a one-pot
synthesis of arylglycine derivatives from the corresponding
imine equivalents (N-Boc-R-amido sulfones 1) using a
combination of TMS-SnBu3 and CsF under a CO2 atmo-
sphere.3 However, there are several limitations to over-
come: (1) a stoichiometric amount of toxic tin waste was
generated after the reaction, (2) only R-aryl-substituted
R-amido sulfones were applicable, and (3) a high tempera-
ture (100 °C) and high pressure (1 MPa = 10 atm) were
necessary to induce efficient carboxylation.4 Thus, we
herein disclose that a less toxic and commercially available
silylboron such as PhMe2Si-Bpin5 is also effective for this
one-pot process so that the intermediate R-amido silane is
more readily activated by CsF than R-amido stannane,
leading to a smooth carboxylation at rt to 100 °C under
0.5 MPa (5 atm) of CO2 pressure. As a result, not only
R-aryl but also R-alkenyl R-amido sulfones were tolerated
to afford the corresponding R-amino acid derivatives in
moderate-to-good yields.
(1) For representative reviews, see: (a) Williams, R. M.; Hendrix,
J. A. Chem. Rev. 1992, 92, 889. (b) Duthaler, R. O. Tetrahedron 1994, 50,
First, we investigated bismetal reagents without a tin
element (Table 1). Several potential bismetal reagents6
such as SiꢀSi, SiꢀGe, BꢀB, and SiꢀB were screened in
DMF as a solvent (entries 1ꢀ5), among which unsymme-
trical bismetals, such as Ph3Si-SiMe3, PhMe2Si-GeMe3,
€
1539. (c) Kreuzfeld, H. J.; Dobler, C.; Schmidt, U.; Krause, H. W. Amino
Acids 1996, 11, 269. (d) Cativiela, C.; Dıaz-de-Villegas, M. D. Tetra-
hedron: Asymmetry 1998, 9, 3517. (e) Maruoka, K.; Ooi, T. Chem. Rev.
2003, 103, 3013. (f) Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42, 4290.
(g) Beak, P.;Johnson, T. A.;Kim, D. D.;Lim, S. H.Top. Organomet. Chem.
ꢀ
2003, 5, 139. (h) Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584.
(2) For reviews on CO2 incorporation reactions, see: (a) Braunstein,
P.; Matt, D.; Nobel, D. Chem. Rev. 1988, 88, 747. (b) Sakakura, T.; Choi,
J.-C.; Yasuda, H. Chem. Rev. 2007, 107, 2365. (c) Mori, M. Eur. J. Org.
Chem. 2007, 4981. (d) Correa, A.; Martın, R. Angew. Chem., Int. Ed.
2009, 48, 6201. (e) Riduan, S. N.; Zhang, Y. Dalton Trans. 2010, 39,
3347. (f) Boogaerts, I. I. F.; Nolan, S. P. Chem. Commun. 2011, 47, 3021.
(g) Ackermann, L. Angew. Chem., Int. Ed. 2011, 50, 3842. (h) Zhang, Y.;
Riduan, S. N. Angew. Chem., Int. Ed. 2011, 50, 6210. (i) Cokoja, M.;
(3) (a) Mita, T.; Chen, J.; Sugawara, M.; Sato, Y. Angew. Chem., Int.
Ed. 2011, 50, 1393. (b) Mita, T.; Higuchi, Y.; Sato, Y. Chem.;Eur.
J., doi: 10.1002/chem.201202332.
(4) Mita, T.; Sugawara, M.; Hasegawa, H.; Sato, Y. J. Org. Chem.
2012, 77, 2159.
(5) For a convenient synthesis of PhMe2Si-Bpin, see: Suginome, M.;
Matsuda, T.; Ito, Y. Organometallics 2000, 19, 4647.
(6) For a review on bismetal reagents, see: Beletskaya, I.; Moberg, C.
Chem. Rev. 2006, 106, 2320.
€
Bruckmeier, C.; Rieger, B.; Herrmann, W. A.; Kuhn, F. E. Angew.
Chem., Int. Ed. 2011, 50, 8510.
r
10.1021/ol302952r
Published on Web 12/03/2012
2012 American Chemical Society

and PhMe2Si-Bpin, somewhat promoted the desired one-
pot reaction to afford the corresponding phenyl glycine 2a
in around 10% yield after methyl esterification with
CH2N2 (for the purpose of determination of yields by 1H
NMR analysis and further purification), accompanied by
a trace amount of protodesilylation product 3a. To induce
an efficient silylation of the imine intermediate using
PhMe2Si-Bpin,7 we then examined protic additives such
Scheme 1. Isolation of R-Amido Silane 4a
as H2O, KF HF, (CF3)2CHOH, 2,6-dimethylphenol, pro-
panoic acid, NH4Cl, and TsOH H2O (entries 6ꢀ12). As
3
of protodesilylation product 3 (entries 3 and 4), indicating
that the electronic effect on the aromatic ring is not so
critical for the yields of carboxylation of R-amido silanes in
contrast to our previous system using R-amido stannanes.4
Furthermore, less reactive R-alkenyl substrate 4s was also
compatible when the reaction was conducted at 100 °C
(entries 5 and 6).
3
a result, the use of a catalytic amount of TsOH H2O
3
(20 mol %) gave the best yield and 2a was obtained in
93% yield. Even when the reaction was performed at rt
under 0.5 MPa and ambient CO2 pressure (using a CO2
balloon), the product was still obtained in 91 and 66%
yields, respectively (entries 13 and 14), the trend of which is
different from that of carboxylation of N-Boc-R-amido
stannanes that requires a high temperature (100 °C).3,4
In order to elucidate the intermediate of this one-pot
sequence, reactions were conducted without CO2 (Scheme1).
On the basis of these experimental results, the whole
reactionpathwayofthisone-potprocessisproposedbelow
(Figure 1). Since a higher level of conversion was guaran-
teed at 100 °C (>74%) with at least 3 equiv of CsF
(1 equiv: 22%; 2 equiv: 54%; 3 equiv: 74%; 4 equiv: 75%;
5 equiv: 93%), only 1 equiv of fluoride ion might be suf-
ficient for SiꢀB bond cleavage. Another 1 equiv of CsF
works as a base to facilitate imine formation, and the final
1 equiv is consumed for silicon activation to generate cesium
carbanion 810,11 or fluorosilicate 80, leading to carboxylation
with CO2. Isolation of R-amido silane 4a strongly indicates
that selective boron activation of PhMe2Si-Bpin by CsF
initially occurs because of a stronger BꢀF bond compared
to a SiꢀF bond (bond dissociation energy: 613 kJ/mol for
BꢀF and 565 kJ/mol for SiꢀF).12 To the best of our
knowledge, there are no precedents of the generation of a
silyl anion equivalent being triggered by fluoride through
SiꢀB bond cleavage.13ꢀ15 We believe that a protic additive
would activate imine 6as a Brønsted acid catalyst to promote
its silylation.7,16 HF, which is released during imine
formation, would act as a proton donor to trap the generated
amido anion 7. This protonolysis of 7is a crucial step because
R-carbanion would be hardly generated directly from 7
In the presence of 20 mol % of TsOH H2O, R-amido
3
silane 4a8 was obtained in 67% yield, while no reaction
occurred in the absence of any protic additives.
In contrast, fluoride-mediated carboxylation of 4a with
CO2 proceeded smoothly to afford 2a in excellent yields at
rt both under 0.5 MPa and ambient CO2 even without any
protic additives (Table 2, entries 1 and 2).9 These obser-
vations suggested that protic additives only affected the
formation of R-amido silane. Notably, the use of both
electron-deficient and -rich substrates (4d and 4k) afforded
the products in high yields with suppression of formation
Table 1. Investigation of Bismetals and Protic Additives
yield (%)a
entry
bismetal reagent
additive (20 mol %)
2a
3a
1
Me3Si-SiMe3
Ph3Si-SiMe3
PhMe2Si-GeMe3
pinB-Bpin
ꢀ
ꢀ
11
16
ꢀ
ꢀ
4
Table 2. Investigation of Carboxylations of 4
2
ꢀ
3
ꢀ
1
4
ꢀ
ꢀ
<1
2
5
PhMe2Si-Bpin
ꢀ
10
10
13
8
6
H2O
yield (%)a
7
KF HF
2
3
8
(CF3)2CHOH
2,6-dimethylphenol
C2H5CO2H
1
temp
CO2 (MPa) (°C) time (h)
9
13
25
53
93
91
66
2
entry
R
2
3
10
11
12
13b
14c
2
1
2
3
4
5
6
Ph (4a)
Ph (4a)
0.5
rt
rt
1
1
1
1
3
3
93
90
95
81
<1
68
2
NH4Cl
2
0.1 (1 atm)
0.1
<1
1
TsOH H2O
3
3
3
3
p-Cl-C6H4ꢀ (4d)
rt
TsOH H2O
2
p-OMe-C6H4ꢀ (4k) 0.1
rt
<1
<1
<1
TsOH H2O
5
Me2CdCꢀ (4s)
Me2CdCꢀ (4s)
0.1
0.5
rt
a Yields were determined by 1H NMR analysis using 1,1,2,2-
tetrachloroethane as an internal standard. b The reaction was performed
at rt under 0.5 MPa of CO2. c The reaction was performed at rt under
ambient CO2 pressure (0.1 MPa).
100
a Yields were determined by 1H NMR analysis using 1,1,2,2-
tetrachloroethane as an internal standard.
Org. Lett., Vol. 14, No. 24, 2012
6203

Table 3. Substrate Scope for Substituted R-Aryl Sulfones
A: yield (%)
B: yield (%)
entry substrate (Hammett σ)
2a
3a
2b
3a
1
m-CN (0.62)
m-CF3 (0.46)
p-Cl (0.22)
m-OMe (0.10)
p-F (0.06)
1b
1c
1d
1e
1f
31
37
64
88
79
61
81
74
53
43
10
41
40
29
17
8
69
78
81
82
91
87
87
86
85
79
71c
85
6
6
3
4
3
6
2
5
2
4
1
3
2
3
4
5
11
12
7
Figure 1. Possible reaction pathways.
6
o-F (ꢀ)
1g
1a
1h
1i
7
H (0.00)
8
m-Me (ꢀ0.06)
p-Me (ꢀ0.14)
o-Me (ꢀ)
8
because of the instability of the corresponding 1,2-dianion.4
Because of the higher affinity of fluoride for Si than for
Sn (bond dissociation energy: 565 kJ/mol for SiꢀF and
414 kJ/mol for SnꢀF),12 R-amido silane 4 is more reactive
toward a fluoride anion than is R-amido stannane,4 which
allows the carboxylation of 4a to proceed even at rt.
Next, substrate scope was examined under 0.5 MPa of CO2
pressure (Table 3 and Figure 2). A wide range of R-aryl
R-amido sulfones (1aꢀ1l) attached with electron-deficient as
9
6
10
11
12
1j
1
p-OMe (ꢀ0.28)
1k
1l
5
o-OMe (ꢀ)
5
a Yields were determined by 1H NMR analysis using 1,1,2,2-tetra-
chloroethane as an internal standard. b Isolated yields after column chro-
matography using 10% KF/SiO2 as a stationary phase. c Reaction time: 16 h.
well as -rich substituents on the aromatic rings with
different Hammett σ-values were all active in con-
trast to the previous system3 in which protodestannyla-
tion products were increased in response to the electron
deficiency of aromatic rings, while final carboxylation
hardly proceeded for electron-donating substrates (Table 3,
methodA3 versus B).4 Inaddition, stericallymorecrowded
ortho-substitutions also gave high yields (1g, 1j, and 1l).
It is noteworthy that cyano functionality, which is not
tolerable in the conventional Strecker synthesis, remained
intact in this sequence. Highly electron-donating substrates
1k and 1l, which had been sluggish for the previous system
(10 and 41%),3 were also reactive (71 and 85%).
Moreover, methylene catechol 1m, both R- and
β-naphthalene (1n and 1o), and heteroaromatic substrates
possessing 2-thienyl and 2-furyl groups (1p and 1q) were all
tolerated (Figure 2). Furthermore, one-pot reactions of
electron-rich 3-furyl sulfone 1r as well as substrates
having alkenyl groups 1sꢀ1w produced the correspond-
ing R-amino acid derivatives in moderate yields even
though they still needed a high temperature condition
(100 °C). 3-Furyl and these alkenyl substrates were
(7) (a) Levin., V. V.; Dilman, A. D.; Belyakov, P. A.; Struchkova,
M. I.; Tartakovsky, V. A. Eur. J. Org. Chem. 2008, 5226. (b) Gritsenko.,
R. T.; Levin, V. V.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.;
Tartakovsky, V. A. Tetrahedron Lett. 2009, 50, 2994. (c) Kosobokov,
M. D.; Dilman, A. D.; Struchkova, M. I.; Belyakov, P. A.; Hu, J. J. Org.
Chem. 2012, 77, 2080.
(8) (a) Ballweg, D. M.; Miller, R. C.; Gray, D. L.; Scheidt, K. A. Org.
€
Lett. 2005, 7, 1403. (b) Vyas, D. J.; Frohlich, R.; Oestreich, M. Org. Lett.
2011, 13, 2094.
(9) Carboxylations of C(sp3)-Si bonds by a fluoride were only
achieved using specific substrates such as 1-cyano-1-trimethylsilyl-
cyclopropane and (perfluoroalkyl)trimethylsilanes. See: (a) Ohno, M.;
Tanaka, H.; Komatsu, M.; Ohshiro, Y. Synlett 1991, 919. (b) Singh,
R. P.; Shreeve, J. M. Chem. Commun. 2002, 1818. (c) Babadzhanova,
L. A.; Kirij, N. V.; Yagupolskii, Y. L. J. Fluorine Chem. 2004, 125, 1095.
(d) Petko, K. I.; Kot, S. Y.; Yagupolskii, L. M. J. Fluorine Chem. 2008,
129, 301. For fluoride-mediated carboxylations of C(sp2)-Si bonds, see:
(e) Effenberger, F.; Spiegler, W. Chem. Ber. 1985, 118, 3900. For a recent
achievement of carboxylation of benzylic silanes using CO2, see:
(f) Mita, T.; Michigami, K.; Sato, Y. Org. Lett. 2012, 14, 3462.
(10) Optically active 4a (97% ee) was synthesized according to the
reported procedure (ref 8a) and subjected to the fluoride-mediated
carboxylation. As a result, 2a was obtained in racemic form, indicating
that carboxylation would proceed via a benzylic anion species 8 rather
than a fluorosilicate 80.
(11) For the stabilization of lithium carbanion by a Boc group, see:
Park, Y. S.; Beak, P. J. Org. Chem. 1997, 62, 1574.
(12) Emsley, J. The Elements, 3rd ed.; Oxford University Press:
New York, 1998.
(13) For transition metal (Rh or Cu)-catalyzed SiꢀB cleavage to
generate silyl anion equivalents, see: (a) Walter, C.; Auer, G.; Oestreich,
M. Angew. Chem., Int. Ed. 2006, 45, 5675. (b) Walter, C.; Oestreich, M.
(14) For silyl anion generation triggered by a fluoride through SiꢀSi
bond cleavage, see: (a) Hiyama, T.; Obayashi, M.; Mori, I.; Nozaki, H.
J. Org. Chem. 1983, 48, 912. (b) Hiyama, T.; Obayashi, M. Tetrahedron
Lett. 1983, 24, 4109. (c) Hiyama, T.; Obayashi, M.; Sawahata, M.
Tetrahedron Lett. 1983, 24, 4113.
€
Angew. Chem., Int. Ed. 2008, 47, 3818. (c) Walter, C.; Frohlich, R.;
Oestreich, M. Tetrahedron 2009, 65, 5513. (d) Vyas, D. J.; Oestreich, M.
Angew. Chem., Int. Ed. 2010, 49, 8513. (e) Lee, K.-S.; Hoveyda, A. H.
J. Am. Chem. Soc. 2010, 132, 2898. (f) Welle, A.; Petrignet, J.; Tinant, B.;
Wouters, J.; Riant, O. Chem.;Eur. J. 2010, 16, 10980. (g) Ibrahem, I.;
(15) For borylation of imines using pinB-Bpin by a methoxide anion
ꢀ
without transition metal catalysts, see: Sole, C.; Gulyas, H.; Fernandez,
ꢀ
ꢀ
E. Chem. Commun. 2012, 48, 3769.
ꢀ
Santoro, S.; Himo, F.; Cordova, A. Adv. Synth. Catal. 2011, 353, 245.
(h) Kleeberg, C.; Feldmann, E.; Hartmann, E.; Vyas, D. J.; Oestreich,
M. Chem.;Eur. J. 2011, 17, 13538. (i) Calderone, J. A.; Santos, W. L.
Org. Lett. 2012, 14, 2090. For a transition-metal-free method, see:
(j) O’Brien, J. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 7712.
(16) It is also possible that the boron atom is prone to be activated by
a fluoride through the coordination of pinacol oxygen to a protic
additive. See: Awano, T.; Ohmura, T.; Suginome, M. J. Am. Chem.
Soc. 2011, 133, 20738.
6204
Org. Lett., Vol. 14, No. 24, 2012

Scheme 3. Salt Formation with (R)-1-Phenethylamine and
Optical Resolution of the Salt
Figure 2. Substrate scope for other arenes and heteroarenes as
well as 3-furyl and alkenyl sulfones using method B (PhMe2Si-
Bpin (1.1 equiv), CsF (5 equiv), TsOH H2O (20 mol %), CO2
(0.5 MPa), DMF, 3 h, then CH2N2). Isolated yields are shown
unless otherwise noted. a The yield was determined by 1H NMR
analysis using 1,1,2,2-tetrachloroethane as an internal standard.
crude mixture was treated with H2O2 in aq citric acid to
convert it into benzenesulfonic acid. In this stage, separation
of the R-amino acid from these sulfonic acids worked very
well, and the resulting extract was treated with (R)-1-
phenethylamine to afford the corresponding pure diaste-
reomer mixture salt 10 in 82% yield as white precipitates.
This salt 10can be transformed into chiral (S)-N-Boc-phenyl
glycine (Boc-PGL) following a conventional optical resolu-
tion by simple recrystallizations.18
3
Scheme 2. Derivatization of Product 2s
In summary, we could successfully utilize PhMe2Si-Bpin
for one-pot R-amino acid synthesis from R-amido sulfones
through CO2 incorporation. Addition of a catalytic amount
of a protic additive plays a crucial role in efficient silylation.
Compared to the previous system using TMS-SnBu3, toxic
organotin reagents could be avoided, and the yields of
R-amino acids were generally higher. In addition, substrate
scope was expanded to tolerate R-alkenyl R-amido sul-
fones, which is a big advantage for replacement with
PhMe2Si-Bpin. The product obtained by this procedure
was successfully transformed into several R-amino acids
within two steps. Furthermore, without purification by
silica gel column chromatography, amino acids were
easily converted to their (R)-1-phenethylamine salts, which
would then provide chiral phenyl glycine after recrystalliza-
tions. Examination of catalytic enantioselective variants of
this transformation is now actively ongoing.
totally inactive under the previous condition,3 highlight-
ing the successful use of PhMe2Si-Bpin.17
Considering the synthetic utility of this one-pot reaction,
R-amino acid derivative 2s obtained by this procedure was
transformed into several useful R-amino acids (Scheme 2).
N-Boc-leucine was obtained in 96% yield by hydrogena-
tion of 2s. N-Boc-serine was obtained in 60% yield
through ozonolysis with O3 followed by reduction with
NaBH4. N-Boc-glycine was synthesized through Tsujiꢀ
Wilkinson decarbonylation from the same intermediate 9.
Although their amino acids are racemic, it is noteworthy that
these simple manipulations enable the synthesis of these basic
R-amino acids only in a few steps using CO2 gas.
Finally, we demonstrated practical preparation of
R-amino acids without purification by silica gel column
chromatography (Scheme 3). After completion of the
reaction, 1 equiv of benzenesulfinic acid and 0.2 equiv of
TsOH existed in the reaction mixture as acidic components
in addition to the desired N-Boc-R-amino acid. However,
benzenesulfinic acid could not be removed by simple extrac-
tion with Et2O from aq citric acid solution. Therefore, the
Acknowledgment. This work was financially supported
by Grants-in-Aid for Young Scientists (B) (No. 24750081)
and for Scientific Research (B) (No. 23390001) from the
Japan Society for the Promotion of Science (JSPS), by a
Grant-in-Aid for Scientific Research on Innovative Areas
“Molecular Activation Directed toward Straightforward
Synthesis (No. 23105501)” from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan, by
Nissan Chemical Industries Ltd., and by the Uehara
Memorial Foundation.
Supporting Information Available. Details of experi-
mental procedures and physical properties of new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Although the intermediate R-amino silane 4 was produced
smoothly when using R-alkyl sulfones, the final carboxylation reaction
did not proceed at all. See the Supporting Information for details.
(18) (a) Lipkowski, A. W. Pol. J. Chem. 1981, 55, 1725. For the use of
1-phenethylamine as a resolving agent, see: (b) Juaristi, E.; Escalante, J.;
ꢀ
Leοn-Romo, J. L.; Reyes, A. Tetrahedron: Asymmerty 1998, 9, 715.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 24, 2012
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