Organic base-catalyzed stereodivergent synthesis of (R)- and (S)-3-amino-4,4,4-trifluorobutanoic acids

Article abstract of DOI:10.1039/c2cc30627a

Organic base-catalyzed reaction of (S)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine with dialkyl malonates was found to be effective for synthesis of both (S,S_S) and (R,S_S) β-aminomalonates in high yield with good to excellent

Full text of DOI:10.1039/c2cc30627a

View Online / Journal Homepage / Table of Contents for this issue
This article is part of the
Organocatalysis
web themed issue
Guest editors: Professors Keiji Maruoka, Hisashi
Yamamoto, Liu-Zhu Gong and Benjamin List
All articles in this issue will be gathered together online at
www.rsc.org/organocatalysis

Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 4124–4126
www.rsc.org/chemcomm
COMMUNICATION
Organic base-catalyzed stereodivergent synthesis of (R)- and
(S)-3-amino-4,4,4-trifluorobutanoic acidswz
Norio Shibata,*a Takayuki Nishimine,a Naoyuki Shibata,a Etsuko Tokunaga,a
Kosuke Kawada,b Takumi Kagawa,b Alexander E. Sorochinskycde and
Vadim A. Soloshonok*de
Received 28th January 2012, Accepted 5th March 2012
DOI: 10.1039/c2cc30627a
Organic base-catalyzed reaction of (S)-N-tert-butanesulfinyl
(3,3,3)-trifluoroacetaldimine with dialkyl malonates was found
to be effective for synthesis of both (S,SS) and (R,SS) b-amino-
malonates in high yield with good to excellent diastereoselectivity
(76–98% de). The products of this Mannich reaction provide
direct access to b-trifluoromethyl-b-alanine of either (R) or (S)
absolute configuration.
In recent years, a fast-growing number of fluorine-containing
pharmaceutical products have generated a great deal of
research activity focusing on preparation of structurally varied
and selectively fluorinated compounds.1 Of particular interest
are fluorine-containing biologically relevant amino derivatives,
such as a- and b-amino acids.2 In the case of b-amino acids,
there is a significant additional interest related to virtually
unexplored potential of these compounds in the spectacular
science of b-peptides.3 One of the synthetically important
targets in a series of b-fluoroalkyl-b-amino acids is 3-amino-
4,4,4-trifluorobutanoic acid 1 (Scheme 1). b-Alanine 1 is used as
a key structural fragment in the design of c[CH(CF3)NH]-retro
peptides4 and can be easily elaborated to a variety of other
biologically important derivatives such as sulfazecin analogues,
b-lactams and a,b-disubstituted b-amino acids.5 According to
the literature methods enantiomerically pure (R)- and (S)-b-amino
acid (1) can be obtained via biomimetic transamination of ethyl
4,4,4-trifluoro-3-oxobutanoate6 followed by enzymatic resolution
Scheme 1 General method for the synthesis of (S)- and (R)-1.
of the corresponding N-(2-phenyl)acetyl derivatives.7 Asymmetric
catalytic8 and stoichiometric9 versions of the biomimetic transami-
nation, as well as other chiral auxiliary based approaches,10 allow
preparation of either enantiomer of acid 1 in enantiomerically
enriched form, which can be further purified to the enantio-
merically pure state via SDE under achiral chromatography
conditions.11 Considering these literature methods, one may
agree that there is a critical need for easily executing preparation of
enantiomerically pure acid 1 to realize its significant synthetic and
biochemical potential.
a Department of Frontier Materials, Nagoya Institute of Technology,
Gokiso, Showa-ku, Nagoya, 466-8555, Japan.
Recently, (SS)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetal-
dimine 2 was introduced as a multifunctional chiral synthon
for preparation of potentially a great variety of organic
compounds containing a biologically important a-trifluoro-
methyl amino moiety.12 Importantly, synthesis of imine 2 can
be performed on the industrial scale thus providing a significant
incentive for systematic study of its chemistry and synthetic
applications.12e As one can envision, the target b-amino acid 1
can be obtained simply by the Mannich-type reaction of imine 2
with derivatives of malonic acid 3 followed by decarboxylation of
one of the carboxylic groups (Scheme 1). Operational simplicity
of this approach would render it an attractive alternative to the
existing methods.
E-mail: nozshiba@nitech.ac.jp; Fax: +81-52-735-5442;
Tel: +81-52-735-7543
b Research Laboratory, TOSOH F-TECH, Inc., 4988 Kaisei-cho,
Shunan, Yamaguchi 746-0006, Japan
c Institute of Bioorganic Chemistry & Petrochemistry,
National Academy of Sciences of Ukraine, Murmanska 5, 02094
Kyiv, Ukraine
d Department of Organic Chemistry I, Faculty of Chemistry,
University of the Basque Country UPV/EHU, 20018 San Sebastian,
Spain. E-mail: v.soloshonok@ikerbasque.org
e IKBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures, spectral data and copies of 1H, 19F and 13C NMR spectra
of all compounds. See DOI: 10.1039/c2cc30627a
c
4124 Chem. Commun., 2012, 48, 4124–4126
This journal is The Royal Society of Chemistry 2012

Table 1 Base screeninga
Table 2 Optimization of reaction conditionsa
(R,SS)/
Time/h Temp./1C Yieldb (%) (S,SS)c
Entry Malonate Base Time/h Temp./1C Yieldb (%) (S,SS)/(R,SS)c
Entry Malonate Base
1
2
3
4
5
6
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
TMG 12
GUA 12
BEMP 12
P1-tBu 12
BEMP 25
P1-tBu 24
P2-Et 24
P2-Et 24
P2-Et 24
P2-Et 24
P2-Et 24
P2-Et 24
P2-Et 24
P2-Et 24
rt
rt
rt
rt
82
88
76
73
59
32
61/39
67/33
88/12
91/9
98/2
98/2
99/1
99/1
98/2
499/1
499/1
92/8
499/1
99/1
1
2
3
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3d
n-BuLi
n-BuLi
n-BuLid
n-BuLi
n-BuLi
Et3N
3
2
1
0.25
0.25
rt
85
88
83
94
98
31
87f
47
62
68
85f
67f
86/14
89/11
89/11
89/11
90/10
80/20
88/12
20/80
25/75
30/70
88/12
80/20
ꢀ78
ꢀ78
ꢀ78
ꢀ78
rt
rt
rt
rt
rt
4
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
5e
6
48
7
72e
84e
85e
89e
73e
78e
98e
22e
7
8
9
10
11
12
DMAP 48
i-Pr2EtN 24
8d
9
DBU
DBN
12
12
10
11
12
13
14
DMAP 48
DMAP 48
rt
rt
3g
a
The reactions of (S)-2 (1 equiv.) with dialkyl malonate (1 equiv.)
b
were performed in toluene in the presence of base (10 mol%). Isolated
a
The reactions of (S)-2 (1 equiv.) with diethyl malonate (1 equiv.) were
b
performed in toluene in the presence of base (10 mol%). Isolated
c
total yield of both diastereomers. Determined by 19F NMR analysis.
total yield of both diastereomers. Determined by 19F NMR analysis.
d
c
d
e
20 mol% of n-BuLi was used. 1.2 Equiv. of imine (S)-2 was used.
e
f
1.2 Equiv. of imine (S)-2 was used. Isolated yield of the major
diastereomer.
Isolated yield of the major diastereomer.
Initially we evaluated the use of preprepared lithium enolate
derived from diethyl malonate 3a in the addition to imine 2.
Surprisingly, when the reaction was performed in toluene at
room temperature in the presence of 10 mol% of n-BuLi, used for
generation of the corresponding enolates, the desired addition
product was isolated as a 86/14 mixture of (R,SS)-4a and (S,SS)-5a
diastereomers in 85% yield (Table 1, entry 1). Further screening of
the conditions has shown that an optimal stereochemical outcome
can be obtained in toluene at ꢀ78 1C, producing a mixture of
(R,SS)-4a and (S,SS)-5a in quantitative yield and 90/10 dr (Table 1,
entries 2–5). The effect of the reaction solvent (THF, Et2O) was
also studied suggesting toluene as a solvent of choice. This unique
behavior of n-BuLi as a catalyst could be explained by an
autocatalytic cycle (see ESIz, Fig. S1).
the Hunig’s base-catalyzed reaction, favoring product (S,S )-5a
¨
S
(Table 1, entries 9 and 10). The optimized DMAP-catalyzed
reaction conditions were applied to a number of dialkyl malonates.
Dimethyl malonate 3b provided yield and diastereoselectivity
comparable to that observed for the diethyl ester (Table 1,
entry 11). When di-tert-butyl malonate 3d was used, the reaction
afforded the addition adduct in noticeably lower yield and
diaselectivity (Table 1, entry 12).
With these results in hand, we set for ourselves a next goal of
preparing the diastereomer (S,SS)-5a as the major product in
synthetically meaningful yield. Taking advantage of commercial
availability of numerous quite strong and bulky bases we were
in a position to conduct a systematic study of the diastereo-
selectivity in the reactions between imine 2 and diethyl malonate
3a. The most representative results obtained are collected in
Table 2 and the structures of bases used are given in Fig. 1. In
a series of the reactions catalyzed by TMG, GUA, BEMP and
P1-tBu we observed noticeable dependence of the stereo-
chemical outcome on overall steric bulk of the base used.
Thus, in this series the ratio of diastereomers (S,SS)-5a and
(R,SS)-4a was gradually increased from 61/39 (Table 2, entry 1)
to synthetically useful 91/9, observed in the reaction catalyzed
by quite bulky P1-tBu (Table 2, entry 4). To our satisfaction
both BEMP and P1-tBu catalyzed reactions conducted at
ꢀ78 1C showed noticeably enhanced diastereoselectivity (Table 2,
entries 5 and 6). Further experiments designed to improve the
diastereoselectivity as well as yield of the major diastereomer
(S,SS)-5a allowed us to identify P2-Et as an optimal base catalyst
(Table 2, entries 7 and 8). The optimal reaction conditions proved
general for structurally diverse malonate esters. Unsubstituted
dialkyl malonates reacted with imine 2 to afford the desired
products in greater than 73% yield and with excellent diastereo-
selectivity except for the case of dibenzyl malonate 3e, where
lower diastereoselectivity was observed (Table 2, entries 9–12).
It should be mentioned that diethyl 2-fluoromalonate can be
successfully used under relatively basic reaction conditions
affording the corresponding Mannich product in excellent yield
and the dr value was higher than 99/1 (Table 2, entry 13).
However, methyl-substituted malonate 3g was less reactive,
With the goal of developing a simple, scalable and metal free
Mannich reaction we decided to explore triethylamine (TEA)
as a catalyst for the addition of dialkyl malonates 3 to imine 2.
In this case no preformation of enolates is required for
preparation of the addition products. The reaction with
diethyl malonate 3a in the presence of TEA took place at a
relatively slow rate furnishing the desired addition product as
a mixture of (R,SS)-4a and (S,SS)-5a diastereomers (Table 1,
entry 6). With the aim to improve the yield and ratio of the
diastereomers (R,SS)-4a and (S,SS)-5a, we revisited the reactions
catalyzed by TEA with other organic bases. We found that
synthetically meaningful chemical yield and diastereomeric
excess of (R,SS)-4a can be obtained in the reactions catalyzed
by DMAP at ambient temperature. The major diastereomer
(R,SS)-4a was isolated in 87% yield after column chromato-
graphy (Table 1, entry 7). N,N-Diisopropylethylamine
(Hunig’s base) was our next choice of organic base catalyst
¨
as it is stronger base but much less nucleophilic and therefore
was expected to cause less byproducts formation. Indeed, the
addition reaction catalyzed by Hunig’s base occurred at a
¨
higher rate within 24 h but, most surprisingly, gave the ratio of
diastereomers (R,SS)-4a and (S,SS)-5a, which was opposite to
what we observed in the TEA and DMAP-catalyzed reactions
(Table 1, entry 8). Other strong bases DBU and DBN allowed
complete conversion of the starting materials within 12 h.
The observed ratio of diastereomers was almost the same as in
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4124–4126 4125

Organic Synthesis Based on Reaction Integration) and the Asahi
Glass Foundation (NS).
Notes and references
1 For reviews see: (a) J. Nie, H.-C. Gua, D. Cahard and J.-A. Ma,
Chem. Rev., 2011, 111, 455; (b) D. O’Hagan, Chem. Soc. Rev.,
2008, 37, 308; (c) S. Purser, P. R. Moore, S. Swallow and
V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320.
Fig. 1 Structures of strong and bulky bases.
2 For recent reviews, see: (a) X.-L. Qiu, W.-D. Meng and F.-L. Qinga,
Tetrahedron, 2004, 60, 6711; (b) R. Smits, C. D. Cadicamo, K. Burger
and B. Koksch, Chem. Soc. Rev., 2008, 37, 1727; (c) J. L. Acena,
A. Simon-Fuentes and S. Fustero, Curr. Org. Chem., 2010, 14, 928;
´
(d) V. P. Kukhar, A. E. Sorochinsky and V. A. Soloshonok, Future
Med. Chem., 2009, 1, 793; (e) A. E. Sorochinsky and V. A. Soloshonok,
J. Fluorine Chem., 2010, 131, 127; (f) K. Mikami, S. Fustero,
´ ´
M. Sanchez-Rosello, J. L. Acena, V. A. Soloshonok and
A. E. Sorochinsky, Synthesis, 2011, 3045.
3 (a) D. F. Hook, F. Gessier, C. Noti, P. Kast and D. Seebach,
ChemBioChem, 2004, 5, 691; (b) S. Capone, I. Kieltsch, O. Flogel,
¨
G. Lelais, A. Togni and D. Seebach, Helv. Chim. Acta, 2008,
91, 2035; (c) B. Jaun, D. Seebach and R. I. Mathad, Helv. Chim.
Acta, 2011, 94, 355.
4 (a) P. Bravo, L. Bruche, C. Pasenti, F. Viani, A. Volonterio and
M. Zanda, J. Fluorine Chem., 2001, 112, 153; (b) M. Zanda,
New J. Chem., 2004, 28, 1401.
5 (a) P. F. Bevilacqua, D. D. Keith and J. L. Roberts, J. Org. Chem.,
1984, 49, 1430; (b) J. Jiang, H. Shah and R. J. DeVita, Org. Lett.,
2003, 5, 4101.
Fig. 2 Transition state models
probably because of steric hindrance. In this case yield of the
product was only 22% although diastereoselectivity was as
high as 99/1 dr (Table 2, entry 14).
6 (a) V. A. Soloshonok and T. Ono, Tetrahedron, 1996, 52, 14701;
(b) H. Ohkura, D. O. Berbasov and V. A. Soloshonok, Tetrahedron,
2003, 59, 1647.
7 (a) V. A. Soloshonok, A. G. Kirilenko, V. P. Kukhar and G. Resnati,
Tetrahedron Lett., 1993, 34, 3621; (b) V. A. Soloshonok,
A. G. Kirilenko, N. A. Fokina, I. P. Shishkina, S. V. Galushko,
V. P. Kukhar, V. K. Svedas and E. V. Kozlova, Tetrahedron:
Asymmetry, 1994, 5, 1119.
8 (a) V. A. Soloshonok, A. G. Kirilenko, S. V. Galushko and
V. P. Kukhar, Tetrahedron Lett., 1994, 35, 5063; (b) V. Michaut,
F. Metz, J. M. Paris and J. C. Plaquevent, J. Fluorine Chem., 2007,
128, 500; (c) V. Michaut, F. Metz, J. M. Paris and J. C. Plaquevent,
J. Fluorine Chem., 2007, 128, 889.
9 (a) V. A. Soloshonok, H. Ohkura and M. Yasumoto, J. Fluorine
Chem., 2006, 127, 924; (b) V. A. Soloshonok, H. Ohkura and
M. Yasumoto, J. Fluorine Chem., 2006, 127, 930.
10 (a) P. Davoli, A. Forni, C. Franciosi, I. Moretti and F. Prati, Tetra-
hedron: Asymmetry, 1999, 10, 2361; (b) N. Lebouvier, C. Laroche,
F. Huguenot and T. Brigaud, Tetrahedron Lett., 2002, 43, 2827;
(c) F. Huguenot and T. Brigaud, J. Org. Chem., 2006, 71, 2159;
(d) Y. Ishida, N. Iwahashi, N. Nishizono and K. Saigo, Tetrahedron
Lett., 2009, 50, 1889; (e) P. Bravo, S. Capelli, M. Guidetti, S. V. Meille,
F. Viani, M. Zanda, A. L. Markovsky, A. E. Sorochinsky and V. A.
Soloshonok, Tetrahedron, 1999, 55, 3025; (f) P. Bravo, A. Farina,
M. Frigerio, S. Valdo Meille, F. Viani and V. A. Soloshonok, Tetra-
hedron: Asymmetry, 1994, 5, 987; (g) M. Molteni, A. Volonterio,
G. Fossati, P. Lazzari and M. Zanda, Tetrahedron Lett., 2007, 48, 589.
11 (a) V. A. Soloshonok, Angew. Chem., Int. Ed., 2006, 45, 766; (b) V. A.
Soloshonok and D. O Berbasov, J. Fluorine Chem., 2006, 127, 597;
(c) V. A. Soloshonok and D. O. Berbasov, Chim. Oggi, 2006, 24, 44.
Major diastereomers (R,SS)-4a and (S,SS)-5a were purified by
column chromatography and hydrolyzed under the standard
conditions to furnish target amino acid (R)- and (S)-1 in enantio-
merically pure form. These results demonstrated the synthetic
flexibility of this methodology allowing synthesis of both
(R)- and (S)-1. The absolute stereochemistry of the products
(R)- and (S)-1 was determined by comparison of their chiroptical
properties with the literature data.9,10
Presumably, the observed diastereoselectivity of base-catalyzed
Mannich reaction of diethyl malonate 3a with imine 2 is deter-
mined by the competing two transition states.13 The stereochemical
outcome of n-BuLi-catalyzed reaction could be explained by
formation of chelated transition state model TS 1 involving both
reacting partners linked together through chelation to lithium
(Fig. 2). At the same time DMAP could promote the enolization
of malonates hence chelated transition state TS 2 could be invoked
where the sulfinyl group activates the enol tautomer to undergo
the addition reaction. The activation of dialkyl malonates with
strong bulky bases could be attributed to the formation of
‘‘naked’’ malonate enolate due to the noncoordinating organic
countercation.14 Addition of ‘‘naked’’ enolate to imine 2 is expected
to proceed via a non-chelated transition state model TS 3 thus
explaining the observed change in the stereoselectivity (Fig. 2).
In conclusion, the present study has demonstrated that both
enantiomerically pure (R)- and (S)-configured 3-amino-4,4,4-
trifluorobutanoic acids 1 can be prepared at will, simply by
choosing an appropriate organic base-catalyst for the addition
reaction between chiral imine 2 and diethyl malonate. A high to
excellent stereochemical outcome and simple set of reactions
render the method a valuable synthetic alternative to the reported
approaches.
12 (a) V. L. Truong, M. S. Menard and I. Dion, Org. Lett., 2007,
´
9, 683; (b) V. L. Truong and V. J. Y. Pfeiffer, Tetrahedron Lett.,
2009, 50, 1633; (c) H. Mimura, K. Kawada, T. Yamashita,
T. Sakamoto and Y. Kikugawa, J. Fluorine Chem., 2010,
131, 477; (d) H. Mei, Y. Xiong, J. Han and Y. Pan, Org. Biomol.
¨
Chem., 2011, 9, 1402; (e) G.-V. Roschenthaler, V. P. Kukhar,
I. B. Kulik, M. Yu. Belik, A. E. Sorochinsky, E. B. Rusanov and
V. A. Soloshonok, Tetrahedron Lett., 2012, 53, 539.
13 (a) P. Zhou, B.-C. Chen and F. A. Davis, Tetrahedron, 2004,
60, 8003; (b) M.-A. T. Robak, M. A. Herbage and J. A. Ellman,
Chem. Rev., 2010, 110, 3600.
This study was financially supported in part by Grants-in-Aid
for Scientific Research (21390030, 22106515, Project No. 2105:
´
14 A. Solladie-Cavallo and B. Crescenzi, Synlett, 2000, 327.
c
4126 Chem. Commun., 2012, 48, 4124–4126
This journal is The Royal Society of Chemistry 2012