Highly enantioselective transfer of chirality from a less to a more configurationally unstable stereogenic center. A practical asymmetric synthesis of (fluoroalkyl)amines via biomimetic transamination

Full text of DOI:10.1021/jo970425c

3030
J . Org. Chem. 1997, 62, 3030-3031
fluoroalkyl)amines of high enantiomeric purity via asym-
metric PSR.
High ly En a n tioselective Tr a n sfer of
Ch ir a lity fr om a Less to a Mor e
Con figu r a tion a lly Un sta ble Ster eogen ic
Cen ter . A P r a ctica l Asym m etr ic Syn th esis
of (F lu or oa lk yl)a m in es via Biom im etic
Tr a n sa m in a tion
The starting chiral Schiff bases 3a -e were readily
synthesized by the direct condensation between an ap-
propriate ketone 1a -e and (S)-R-phenylethylamine (2)
(Scheme 1). An important characteristic of these sub-
strates is that they exist as individual anti isomers (by
NMR). For the initial studies of the isomerization of 3a
to 4a , we tried to apply as mild as possible reaction
conditions, since the targeted product 4a is obviously
prone to racemization under the forcing conditions or
when strong base is used.8 Unfortunately, ketimine 3a ,
as well as the rest of the N-(R-phenylethyl) derivatives
3b-e, were found to be totally inert under the conditions
previously established for isomerizations of the N-benzyl
analogs.1b Thus, no isomerization of 3a to 4a was
observed in triethylamine (TEA) solution for more than
1 week. However, at 150 °C the isomerization was
achieved, albeit with a slow reaction rate, to afford
targeted 4a in moderate isolated yield (Table 1, entry 1).
Enantiomeric purity of the product 4a , determined
directly for 4a or for its N-(3,5-dinitrobenzoyl) derivative,
was shown to be 50% ee. Further, we have found that
the addition of DABCO (0.5 equiv) or DBU (0.1 equiv) to
the TEA solution allows the isomerization to be com-
pleted under milder conditions (Table 1, entries 2 and 3)
to give the product 4a with both substantially enhanced
chemical yield and enantiomeric purity. Drawing inspi-
ration from these findings, we performed the isomeriza-
tion in neat DBU. The result was rather impressive: the
isomerization was completed at 50 °C after only 1 h,
furnishing the product 4a in excellent chemical yield and
with markedly enhanced enantiomeric purity (Table 1,
entry 4). Lowering of the reaction temperature (Table
1, entry 5) decreased the isomerization rate but afforded
the product in higher enantiomeric purity (Table 1, entry
5 vs 4). While working with the isomerization of 3a to
4a , we noticed that the DBU/substrate ratio has a
dramatic influence on the isomerization rate. This
observation was quite unexpected as it is not consistent
with a purely catalytic role of the base in these isomer-
izations. However, the results in entries 6 and 7 of Table
1 clearly demonstrate that the isomerization rate is a
function of the ratio DBU/3a . At this stage, we can
suggest that DBU, apart from the role of the catalyst,
works as a unique reaction medium facilitating the
isomerization. Whatever the effect of DBU, the synthetic
result was quite valuable: the isomerization of ketimine
3a in neat DBU solution afforded Schiff base 4a in 95%
yield and in 87% ee (Table 1, entry 7). These results
(Table 1) indicate that, as we expected, Schiff base 4a is
configurationally unstable toward the basic conditions,
but, surprisingly, under certain conditions (DBU, 1-2
equiv) isomerization of 3a to 4a occurs with a much
higher rate than the racemization of 4a , allowing its
preparation in both high chemical yield and enantiomeric
purity.
Vadim A. Soloshonok* and Taizo Ono
National Industrial Research Institute of Nagoya,
Hirate-cho 1-1, Kita-ku, Nagoya City,
Aichi Prefecture 462, J apan
Received March 10, 1997
[1,3]-Proton shift reaction (PSR), a reducing agent-free
biomimetic reductive amination,1 is emerging as a con-
venient, preparatively useful generalized method for the
synthesis of various fluorine-containing amino com-
pounds of a wide range of potential biomedicinal and
synthetic applications.2 To achieve the desired transfor-
mation of a carbonyl to an amino group, PSR makes use
of biomimetic transposition3 of an imine functionality via
base-catalyzed azomethine-azomethine isomerization
and thus is conceptually different from the well-tried
purely chemical methodology relying heavily on the use
of external reducing agents.4 However, for that exciting
synthetic potential of PSR to be realized in full, the
asymmetric PSR, allowing for preparing enantiomerically
pure targets, must be developed. On the other hand, the
mechanism of hydrocarbon base-catalyzed azomethine-
azomethine isomerization was shown to involve the
formation of a delocalized 2-azaallyl anion, the evolution
of which to the new covalent state is a function of
thermodynamic preference of the tautomeric Schiff bases
and could be adequately correlated by the Hammett
equation.5 In other words, the equilibrium of the isomer-
ization is shifted toward a more C-H acidic tautomer.
In terms of stereochemistry, it means that the proton
transfer occurs from a less to a more configurationally
unstable stereogenic center. The methodology for such a
kind of asymmetric transformation is virtually undevel-
oped and thermodynamically not allowed.6,7 In this
paper, we report a successful solution to these problems
that allows for an efficient, generalized synthesis of (R-
(1) (a) Soloshonok, V. A.; Kukhar, V. P. Tetrahedron 1996, 52, 6953.
(b) Ono, T.; Kukhar, V. P.; Soloshonok, V. A. J . Org. Chem. 1996, 61,
6563. (c) Soloshonok, V. A.; Ono, T. Tetrahedron 1996, 52, 14701 and
other references on PSR cited therein.
(2) For a general discussion of the biological activity and importance
of fluorinated amino compounds see the following monographs: (a)
Biomedicinal Aspects of Fluorine Chemistry; Filler, R., Kobayashi, Y.,
Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, 1993. (b) Fluorine-
Containing Amino Acids: Synthesis and Properties; Kukhar, V. P.,
Soloshonok, V. A., Eds.; Wiley: Chichester, 1994. (c) Biomedical
Frontiers of Fluorine Chemistry; Ojima, I., McCarthy, J . R., Welch, J .
T., Eds.; American Chemical Society: Washington, D.C., 1996. For the
most recent publications see: (d) Fluoroorganic Chemistry: Synthetic
Challenges and Biomedical Rewards; Resnati, G., Soloshonok, V. A.,
Eds.; Tetrahedron Symposium-in-Print No. 58; Tetrahedron 1996, 52,
1-330.
(3) (a) Snell, E. E. In Chemical and Biological Aspects of Pyridoxal
Catalysis; Fasella, P. M., Braunstein, A. E., Rossi-Fanelli, A., Eds.;
Macmillan: New York, 1963. (b) Pyridoxal Catalysis: Enzymes and
Model Systems; Snell, E. E., Braunstein, A. E., Severin, E. S.,
Torchinsky, Yu, M., Eds.; Interscience: New York, 1968.
(4) For the most recent and comprehensive publication on conven-
tional reductive amination of carbonyl compounds see: Abdel-Magid,
A.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J . Org.
Chem. 1996, 61, 3849 and references cited therein.
(6) (a) J aeger, D. A.; Broadhurst, M. D.; Cram, D. J . J . Am. Chem.
Soc. 1979, 101, 717. (b) Guthrie, R. D.; J aeger, D. A.; Meister, W.;
Cram, D. J . J . Am. Chem. Soc. 1971, 93, 5137. (c) J aeger, D. A.; Cram,
D. J . J . Am. Chem. Soc. 1971, 93, 5153 and other references of this
group cited therein.
(7) Kukhar, V. P.; Soloshonok, V. A.; Galushko, S. V.; Rozhenko, A.
B. Dokl. Akad. Nauk SSSR 1990, 310, 886 (Engl. transl. p 26).
(8) We have shown that forced reaction conditions and strong bases
cause dehydrofluorination of Schiff bases of type 4; see refs 1b and 7.
(5) (a) Cram, D. J .; Guthrie, R. D. J . Am. Chem. Soc. 1966, 88, 5760.
(b) Smith, P. A. S.; Dang, C. V. J . Org. Chem. 1976, 41, 2013. (c) Layer,
R. W. Chem. Rev. 1963, 489.
S0022-3263(97)00425-8 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 10, 1997 3031
Sch em e 1
temperature (21 °C) to give the targeted 4b in highest
chemical yield and in 88% ee (Table 2, entry 3).
Stereochemical discrimination between methyl and
trifluoromethyl groups is always very intriguing. We
have found that isomerization of imine 3c in neat DBU
(1 equiv) occurs smoothly at 60 °C in 18 h to provide 4c
in high chemical yield and in 93% ee (Table 2, entry 4).
Also, in this case, the increase in the ratio DBU/3c
accelerated the isomerization to afford product 4c in the
same ee (Table 2, entry 5). Under the same reaction
conditions, the isomerization of (trifluoromethyl)eth-
ylimine 3d gave the desired product 4d with lower
stereoselectivity (87% ee), suggesting that the enanti-
oselectivity of the proton transfer is dependent on the
size of the substituent at the imine carbon (Table 2,
entries 6 and 7).
In contrast to isomerizations of (trifluoromethyl)imines
3a -d , transformation of perfluoropropyl derivative 3e in
a solution of DBU (1.5 equiv) at 60 °C was accompanied
by a sizable formation of byproducts. However, the
targeted product 4e was isolated in synthetically useful
74% yield and with excellent enantioselectivity (97% ee)
(Table 2, entry 8).
From the data obtained the following important con-
clusions can be drawn at this stage. First, despite the
apparently lower configurational stability of Schiff bases
4a -e than that of starting imines 3a -e,9 the isomeriza-
tion of 3a -e to 4a -e can be conducted with very high
enantioselectivity. Second, the application of the DBU
in a submolar ratio to the starting imine, as the base and
as the solvent, is critical for both the rate and the
stereochemical outcome of the reactions. Finally, the
results obtained highlight the exciting stereodirecting
features of the perfluoroalkyl group (CF3, C3F7). Thus,
this group provides geometrical homogeneity of the initial
imines 3a -e and plays the role of an enantiocontrolling
group in the isomerizations of 3a -e to 4a -e.
In summary, this study has disclosed a unique example
of a highly enantioselective [1,3]-proton transfer from a
less to a more configurationally unstable stereogenic
center. A wide range of synthetic applications of this
asymmetric, reducing reagent-free transamination for
preparing biologically interesting fluoro amino com-
pounds are readily envisaged. The extreme simplicity
of the experimental procedure and the ready availability
of all starting materials, combined with substrate gen-
erality, high chemical, and optical yields of the targeted
products, render this biomimetic approach an immedi-
ately useful alternative to existing methods.10 Worthy
of further investigation are the very intriguing stereo-
directing features of the perfluoroalkyl group. These,
along with the expansion of this methodology to other
classes of carbonyl compounds, are under active study.
Ta ble 1. Op tim iza tion of Rea ction Con d ition s:
Isom er iza tion s of (S)-3a to (R)-4a a
entry
base (equiv)
T, °C time, h yield,b % ee,c %
1
2
3
4
5
6
7
TEAd
150
100
50
50
18
120
30
130
1
7
15
4
64
76
80
98
95
73e
95
50
55
60
77
84
81
87
TEAd/DABCO (0.5)
TEAd/DBU (0.1)
DBU (1)
DBU (1)
DBU (0.5)
DBU (2)
19
19
a
All reactions were run under dry argon atmosphere; 10-1
b
mmol scale. Isolated yield of analytically pure material. c (R)-
Absolute configuration of 4a was determined by optical rotation;
ee values determined by chiral HPLC analysis of N-(3,5-dini-
d
trobenzoyl) derivative. TEA was used as solvent. e Conversion
of 3a to 4a 90%.
Ta ble 2. Asym m etr ic Isom er iza tion s of (S)-3b-d to
(R)-4b-d a
imine
base
T, time, yield,b ee,c
entry
R
Rf
(equiv)
°C
h
%
%
1
2
3
4
5
6
7
8
b
b
b
c
c
d
d
e
Bn CF3
Bn CF3
Bn CF3
Me CF3
Me CF3
DBU (1)
DBU (1)
DBU (2)
DBU (1)
DBU (1.5) 60
DBU (1) 60
DBU (1.5) 60
50
80
21
60
9
2
86
82
93
90
94
87
90
74
88
85
88
93
93
87
87
97
42.5
18
15
18
15
15
Et
Et
CF3
CF3
Me C3F7 DBU (1.5) 60
a
b
All reactions were run under dry argon atmosphere. Isolated
yield of analytically pure material. c Determined by chiral HPLC
analysis of N-(3,5-dinitrobenzoyl) derivatives.
Assuming that the asymmetric outcome of the isomer-
ization might be a function of the stereochemical dis-
crimination between substituents at the imine carbon,
we selected four types of substrates bearing the trifluo-
romethyl group vs benzyl 3b, methyl 3c, ethyl 3d , and
perfluoropropyl vs methyl group 3e, which would allow
us to evaluate the generality of the method. The results
are collected in Table 2. Isomerization of highly enami-
nolizable (trifluoromethyl)benzylimine 3b was of par-
ticular interest as it is known that for hydrocarbon imines
base-catalyzed azomethine-enamine isomerization is a
much more favorable process than relative azomethine-
azomethine prototropy.5c In contrast to this worrisome
expectation, imine 3b was completely isomerized in neat
DBU (1 equiv) at 50 °C for 9 h to give Schiff base 4b in
both high chemical yield and enantiomeric purity (Table
2, entry 1). At an elevated temperature (80 °C), the
isomerization proceeded with a higher reaction rate
furnishing, however, the product 4b in lower yield and
enantiomeric purity (Table 2, entry 2). The application
of 2 equiv of DBU accelerated the isomerization, allowing
us to achieve complete transformation of 3b to 4b at room
Ack n ow led gm en t. V.A.S. thanks Dr. K. Ramig, of
Bristol-Myers Squibb, for proofreading the manuscript.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization of all numbered compounds as
well as N-(3,5-dinitrobenzoyl) derivatives of the corresponding
fluoro amines (7 pages).
J O970425C
(9) It clearly follows from the fact that, for instance, in boiling TEA
product 4a easily undergoes racemization while the starting 3a
remains stereochemically intact; see Table 1.
(10) (a) Asymmetric reduction: Pirkle, W. H.; Hauske, J . R. J . Org.
Chem. 1977, 42, 2436. (b) Classical resolution: Wang, Y.; Mosher, H.
S. Tetrahedron Lett. 1991,32, 987.