Continuous-flow asymmetric biomimetic transamination

Article abstract of DOI:10.1016/j.jfluchem.2009.02.010

This study has demonstrated that conceptually new continuous-flow reaction procedure for biomimetic transamination of perfluoroalkyl-containing ketones is substantially more efficient as compared with conventional in-flask approach, allowing preparation o

Full text of DOI:10.1016/j.jfluchem.2009.02.010

Journal of Fluorine Chemistry 130 (2009) 512–515
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Journal of Fluorine Chemistry
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Short communication
Continuous-flow asymmetric biomimetic transamination
Vadim A. Soloshonok a,b, , Hector T. Catt a,b, Taizo Ono a,b
*
a National Institute of Advanced Industrial Science and Technology (AIST), 2266-98 Anagahora, Shimoshidami, Moriyama-ku, Nagoya, Aichi Prefecture 463-8560, Japan
b Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, United States
A R T I C L E I N F O
A B S T R A C T
Article history:
This study has demonstrated that conceptually new continuous-flow reaction procedure for biomimetic
transamination of perfluoroalkyl-containing ketones is substantially more efficient as compared with
conventional in-flask approach, allowing preparation of the target fluorinated amines with generally
improved chemical yields and enantioselectivity.
Received 31 January 2009
Received in revised form 17 February 2009
Accepted 18 February 2009
Available online 3 March 2009
ß 2009 Elsevier B.V. All rights reserved.
Dedicated to Academician of National
Academy of Sciences of Ukraine,
Professor Valerii Pavlovich Kukhar
(Institute of Bioorganic Chemistry
and Petrochemistry of National Academy
of Sciences of Ukraine) on the occasion
of his 67th birthday.
Keywords:
Asymmetric synthesis
1,3-Proton shift reaction
On-column reactions
Continuous process
Biomimetic transamination
Reductive amination
Fluorine-containing amino compounds
In recent decade the development of synthetic methodology
mimicking biological processes has been at the forefront of organic
chemistry [1]. The major advantage of the biomimetic approach
over traditional, purely chemical methods is that it is based on
compound 2 and nucleophilic amine 1 or, vice versa, electrophilic
amine 1 and nucleophilic carbonyl compound 2. Since the latter
option is virtually impossible, the realistic synthetic application of
biological transamination should focus on the maximum possible
differences between the electrophilicity of a carbonyl compound 2
and nucleophilicity of an amine 1. However, there is still a great
degree of synthetic flexibility as one may target preparation of
transition metal-free organocatalytic reactions, offering
a
‘‘greener’’ and operationally convenient [2] methodological option
for preparation of various organic compounds. In particular, the
biological cofactor pyridoxal 50-phosphate-catalyzed transamina-
tion [3] inspired many organic chemists to discover its mechanism
[4] and develop its chemical models [5] for possible synthetic
applications (Scheme 1).
The major issue in using the principle of biological transamina-
tion is the control of equilibrium between imines 3 and 4, which
serves as an intramolecular reduction–oxidation step. Usually, this
type of azomethine–azomethine isomerization occurs quite
sluggishly and requires application of relatively strong base-
catalyst [5b]. In general, the control of equilibrium between 3 and 4
could be provided in combination of highly electrophilic carbonyl
carbonyl compound
6 (oxidative deamination) or amine 1
(reductive amination). Both processes were successfully realized
with the development of particularly electrophilic carbonyl
compounds 2 [6] and amines 5, structurally mimicking the
enzymatic pyridoxal [7,8].
Of particular importance is application of this biomimetic
methodology for reductive amination of fluorinated carbonyl
compounds (Scheme 2). Due to the strong electron-withdrawing
nature of fluorine the equilibrium between the corresponding
imines 3 and 4 is virtually completely shifted towards 4 rendering
this reaction extraordinary general and truly practical for
preparation of fluorine-containing amines and amino acids. Thus,
as shown in Scheme 2, fluoroalkyl/fluoroaryl aldehydes and
ketones 7 (R = H, alkyl, aryl) can be efficiently transaminated to
the corresponding amines 8 using benzylamine, as a reducing
* Corresponding author.
E-mail address: vadim@ou.edu (V.A. Soloshonok).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.02.010

V.A. Soloshonok et al. / Journal of Fluorine Chemistry 130 (2009) 512–515
513
Scheme 1. General scheme for biomimetic oxidative deamination/reductive amination.
Scheme 2. Biomimetic reductive amination of fluorinated carbonyl compounds.
reagent, and triethylamine as a catalyst [9]. Under the similar
As shown in Scheme 2, the literature procedure [15f] includes
condensation of ketones 7 with chiral amine 14 to form imines 15
followed by their DBU-catalyzed isomerization to Schiff bases 16,
which can be easily hydrolyzed to furnish the target amines 12. The
key step of the process, the transformation of 15 to 16, is virtually
irreversible and notably enantioselective (up to 97% ee) making
this reaction practically useful. However, there are two general
complications in this isomerization stemming from high C–H
acidity (driving force of reaction) of compounds 16. Thus,
derivatives 16 are substantially less configurationally stable, as
compared with 15, and therefore prone to racemization, especially
in the presence of strong base, like DBU. For instance, in the
transformation of 15 (R = Ph, CF = CF3) to corresponding 16, the
stereochemical out come can range from 50 to 87% ee, depending
on the reaction conditions used (temperature, nature and amount
of base). Furthermore, the high C–H acidity of 16 is also the cause
for some dehydrofluorination leading to decreased chemical yields
(ranging from 64 to 98%) [15f] (Scheme 3).
conditions
amino acids 9 [10,11]. Preparation of
a
-keto carboxylic acids 7 (R = COOH) give rise to
-amino acids 10 from
a
b
-
-
b
keto acids 7 (R = CH2COOH), requires a stronger base but can be
performed in excellent chemical yields [12,13]. Of particular
interest is a unique example of double biomimetic transamination
of fluorinated acids 7 (R = OH) to amines 11. In this case, the seven-
step process involves two triethylamine-catalyzed 1,3-proton shift
transfers as well as triphenylphosphine-catalyzed chlorotropic
shift, thus allowing both
used as ‘‘reducing reagents’’ [14]. Asymmetric version of this
process with application of -(phenyl)ethylamine allows prepara-
a-protons of starting benzylamine be
a
tion of the corresponding fluorinated amines and amino acids 12 in
relatively high enantiomeric purity [15].
Recently, our group has explored a new dimension in this area
with the development of continuous-flow reaction conditions for
biomimetic reductive amination of fluorinated carbonyl com-
pounds 7 to amines 13 (R = Ph, Alkyl), using silica-adsorbed DBU as
catalyst for on-column process [16]. Taking into account that the
corresponding continuous-flow process cannot be realized using
the conventional reductive amination methods, this new direction
takes truly full advantage of the intramolecular reduction/
oxidation nature of biomimetic transamination. As a next logical
step, we report here the first example of asymmetric biomimetic
reductive amination under continuous-flow reaction conditions.
In principle, these problems cannot be solved under the
conventional ‘‘in-flask’’ conditions as the issues of chemical
yield-enantioselectivity vs. conditions (base-temperature–time)
are naturally inter-convened and one factor cannot be improved
without sacrifice of the other. Ideally, to solve these complications
compounds 16 should be isolated from the reaction medium
immediately upon their formation. In this regard, the continuous-
Scheme 3. Asymmetric biomimetic reductive amination of fluorinated carbonyl compounds.

514
V.A. Soloshonok et al. / Journal of Fluorine Chemistry 130 (2009) 512–515
Scheme 4. Continuous-flow asymmetric biomimetic transamination.
flow reaction conditions can offer a reasonable promise as the
exposure products 16 to the base can be controlled by the elution
rate.
unstable (dehydrofluorination) in the series compound 16e
noticeable increase in chemical yield was observed (from 74 to
87%).
To realize this possibility we built the continuous-flow reaction
column shown in Scheme 4. The difference from the previously
reported [16] design is that the DBU-catalyzed isomerization of
compounds 16 take place at substantially slower rates as
compared with the corresponding N-benzyl derivatives. Therefore,
we need to add the ‘‘heating zone’’ unit, which can be easily
implemented using a usual heating spiral or a mantle, covering
completely the ‘‘reaction zone’’ and about half of the ‘‘protection
zone’’.
After some experimentation the optimal column construction
for the continuous-flow reactions was found as follows: the usual
Pyrex-glass column was charged about 3/4 of the volume with a
silica gel (200–300 mesh) (hexanes). Next, a calculated amount of
DBU [17] (0.30 wt.% of the whole amount of silica gel) in a solution
of dichloromethane was charged carefully onto the top and
allowed to percolate down to the surface. Then an additional
amount (1/4 of the whole amount) of silica gel was charged
carefully onto the column. A heating mantle was attached to the
column and the temperature was set at 50 8C. Imines 15a–e were
charged onto top of the column as a solution (10 mol%) in hexanes/
acetonitrile (4/1). The rate of elution vs. completion of the
isomerization (19F NMR) was a key issue to limit to the very
minimum essential the time of the products 16 exposure to the
DBU in the ‘‘reaction zone’’. After painstaking experimentations we
found that, for the indicated above amount of DBU and the imine
15 concentration, the elution rate about 1 drop per three seconds
provided for >95% conversion of starting compounds 15a–e to the
imines 16a–e. The structure and purity of the products 16a–e were
confirmed by NMR and their enantiomeric composition was
determined using SUMICHIRAL OA-4500; eluent: n-hexane/
dichloromethane/ethanol = 60/30/10.
As it follows from the data presented in Scheme 4, the chemical
and stereochemical outcome of these continuous-flow reactions,
to our delight, was noticeably positive as in most of cases the
chemical yield and/or enantioselectivity was improved. For
instance, in the most difficult case of preparation of derivative
16a, in which the C–H acidity is the highest in the series, we
obtained the product 16a with similar yield but with substantially
increased enantioselectivity, from 77 [15f] to 93% ee. In the case of
16b, containing benzyl and trifluoromethyl groups we were able to
improve both chemical yield (from 86 to 93%) and stereoselectivity
(from 88 to 91% ee). Interestingly, no visible advance was observed
in preparation of methyl/trifluoromethyl derivative 16c, while its
ethyl analog 16d was obtained with both, albeit slightly, improved
yield and enantioselectivity. Finally, in the case of the most
These preliminary data strongly suggest that the continuous-
flow reaction conditions are obviously advantageous over tradi-
tional in-flack approach for preparation of biologically important
fluorinated amino compounds via asymmetric biomimetic trans-
amination. Optimization, generalization and advancement of this
novel continuous-flow reaction procedure are currently under
investigation and will be reported in due course.
In summary, we demonstrated that conceptually new con-
tinuous-flow reaction procedure for biomimetic transamination
of perfluoroalkyl-containing ketones is substantially more effi-
cient as compared with conventional in flask approach, allowing
preparation of the target fluorinated amines with generally
improved chemical yields and enantioselectivity. We are con-
fident that this new dimension in the practice of biomimetic
transamination is an important step-up in the development of
truly practical and environmentally benign metal-free synthetic
methodology.
Acknowledgments
This work was supported by the Department of Chemistry and
Biochemistry, University of Oklahoma. The authors gratefully
acknowledge generous financial support from Central Glass
Company (Tokyo, Japan) and Ajinomoto Company (Tokyo, Japan).
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