Direct racemic mixture synthesis of fluorinated amino acids by perfluoroalkyl radical addition to dehydroamino acids terminated by asymmetric protonation

Article abstract of DOI:10.1002/ejoc.201000017

The development of efficient methods for the synthesis and purification of chiral organic compounds is a challenge in modern science and technology. Pharmaceuticaliy and agrochemically important compounds are especially required in optically pure form. We report the racemic mixture synthesis of β-perfluoroalkyl α-amino acids, which is based on the Inmediated addition of perfluoroalkyl radicals to dehydroamino acids followed by asymmetric protonation. All the enantiomers can be separated by using a single chiral HPLC column, without orthogonal use of a fluorous column.

Full text of DOI:10.1002/ejoc.201000017

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000017
Direct Racemic Mixture Synthesis of Fluorinated Amino Acids by
Perfluoroalkyl Radical Addition to Dehydroamino Acids Terminated by
Asymmetric Protonation
Tomoko Yajima,*[a] Takayuki Tonoi,[a][‡] Hajime Nagano,[a] Yuichi Tomita,[b] and
Koichi Mikami*[b]
Keywords: Protonation / Chirality / Amino acids / Radical reactions / Indium
The development of efficient methods for the synthesis and
purification of chiral organic compounds is a challenge in
modern science and technology. Pharmaceutically and agro-
chemically important compounds are especially required in
optically pure form. We report the racemic mixture synthesis
of β-perfluoroalkyl α-amino acids, which is based on the In-
mediated addition of perfluoroalkyl radicals to dehy-
droamino acids followed by asymmetric protonation. All the
enantiomers can be separated by using a single chiral HPLC
column, without orthogonal use of a fluorous column.
resultant α-amino ester radicals, although highly electro-
philic perfluoroalkyl radicals are recognized to be less fa-
vorable to add to electron-deficient acrylates.[3] (2) The radi-
cal addition reaction can be terminated by asymmetric pro-
tonation[7] of the resultant α-amino ester enolates generated
by single-electron transfer. (3) In RMS,[4] simultaneous de-
mix, enantioseparation, and identification of amino esters
having perfluoroalkyl substituents rather than fluorous tags
solve the problems in solution-phase[8] combinatorial[9] syn-
thesis by using only one single chiral HPLC column[10] and
no orthogonal use of a fluorous column.[4,11]
Introduction
Fluorinated amino acids are one of the most promising
non-proteinogenic amino acids and have gained increased
attention not only in pharmaceuticals but also in supra-
molecular science.[1] Specifically, β-perfluoroalkyl α-amino
acids are highly expected to provide new functional com-
pounds such as Teflon proteins,[2] because of their chemical/
thermal stability and unique natures: Their hydrophobicity,
bulkiness, and electronegativity are adjustable by introduc-
tion of a variety of perfluoroalkyl groups. However, ef-
ficient synthetic methods for chiral fluorinated amino acids
are quite limited.[1] We reported the synthesis of chiral β-
perfluoroalkyl α-iodo amides by a chiral auxiliary method[3]
and the racemic mixture synthesis (RMS)[4] of fluorinated
α-iodo esters that could be enantioseparated[5] as precursors
for α-amino acids.
Here we report direct access to chiral β-perfluoroalkyl
α-amino acids and the procedure is based on the indium-
mediated addition of perfluoroalkyl radicals to dehy-
droamino acids; the reaction sequence is terminated by
asymmetric protonation (Scheme 1). The present approach
to chiral β-perfluoroalkyl α-amino acids features: (1) The
indium-mediated radical addition of perfluoroalkyl iodide
to dehydroamino acids to directly provide fluorinated
amino esters by captodative synergistic stabilization[6] of the
Scheme 1. Direct synthesis of fluorinated α-amino acids.
Results and Discussion
The perfluoroalkyl radical addition[12] was first investi-
gated on N-benzyloxycarbonyl dehydroamino acid methyl
ester[13] (1a). Radical initiators such as Et3B, Bu3SnH, and
AIBN were totally ineffective. Reductively induced radical
conditions were then investigated (Table 1). To a solution
of dehydroamino ester 1a and n-C4F9I (5 equiv.) was added
a reductant (4 equiv.), and the reaction mixture was then
[a] Department of Chemistry, Ochanomizu University,
2-1-1 Otsuka, Tokyo 112-8610, Japan
E-mail: yajima.tomoko@ocha.ac.jp
stirred at 20 °C. When the reaction was performed with
[b] Department of Applied Chemistry, Tokyo Institute of Technol-
ogy,
[16]
Pd(PPh3)4,[14] RhCl(PPh3)3,[15] or RuCl2(PPh3)3
a com-
2-12-1 Ookayama, Tokyo 152-8552, Japan
E-mail: mikami.k.ab@m.titech.ac.jp
plex mixture of products was obtained (Table 1, Entries 1–
3). The reaction with zinc[17] gave the desired perfluoroalk-
ylated product in 11% (Table 1, Entry 4). The use of in-
[‡] Current address: Department of Chemistry, Tottori University,
4-101 Koyama-Minami, Tottori 680-8550, Japan
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T. Yajima, T. Tonoi, H. Nagano, Y. Tomita, K. Mikami
SHORT COMMUNICATION
dium[18] instead of Zn increased the yield up to 48% various perfluoroalkyl radicals was then investigated with
(Table 1, Entry 5), although there has been no report on the Cbz-protected dehydroamino ester 1a. Various lengths of
Michael addition of RfI (Rf = perfluoroalkyl) mediated by perfluoroalkyl radicals can be directly introduced into the
In.
dehydroamino ester, with the trifluoromethyl radical in par-
ticular (CF3 59%, n-C3F7 45%, n-C4F9 54%).
Table 1. Reductively induced radical addition of C4F9I.
Table 3. Radical addition of C4F9I to various dehydroamino esters.
Entry
Reductant
Solvent
% Yield
[a]
1
2
3
4
5
Pd(PPh3)4
RhCl(PPh3)3
RuCl2(PPh3)3
Zn
MeOH
MeOH
MeOH
CH2Cl2
MeOH
–
–
–
[a]
Entry Substrate
R1
R2
R3
% Yield
[a]
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
H
H
H
H
H
Bn
Bn
tBu
Et
Bn
Et
Me
Bn
Me
Me
H
54
41
22
28
16
–
11
48
In
[a] Complex mixture of products.
The reaction conditions were then optimized by using
In as a radical initiator (Table 2). When the reaction was
performed with the use of protic polar solvents such as
iPrOH or MeOH the desired products were obtained
(Table 2, Entries 1, 2, and 9). However, the reaction did not
take place in the presence of water[19] (Table 2, Entries 7
and 8). In aprotic (Table 2, Entries 3 and 4) or less polar
(Table 2, Entries 5 and 6) solvents, the reaction did not pro-
ceed. The best result was obtained in MeOH at 50 °C when
n-C4F9I (8 equiv.) and In (7 equiv.) were used to generate
the perfluorobutyl radical through single-electron trans-
fer[18] (Table 2, Entry 11). Indeed, in the presence of
TEMPO as a radical scavenger, the reaction did not proceed
at all (vide infra; Table 2, Entry 12).
Bn
Bn
The reaction can be recognized by a single-electron
transfer radical mechanism (Scheme 2). Indium[18] gener-
ates a perfluoroalkyl radical by single-electron transfer. In-
deed, TEMPO as a radical scavenger, totally retarded the
addition (vide supra) (Table 2, Entry 12). The perfluoro-
alkyl radical adds to the dehydroamino acid to give the cap-
todatively stabilized[6] α-amino ester radical intermediate.
Indium further reduces the perfluoroalkylated α-amino es-
ter radical intermediate through single-electron transfer to
give an ester enolate and final protonation gives the desired
hydroperfluorinated product. Indeed, when the reaction
was performed in [D4]MeOH as a solvent, the correspond-
ing α-deuterated product was produced.
Table 2. In-mediated radical addition of C4F9I.
Entry
Solvent
% Yield
1
2
3
4
iPrOH
THF
MeCN
12
24
14
0
Scheme 2. Indium-mediated single-electron transfer mechanism.
DMF
5
6
7
8
CH2Cl2
toluene
H2O
0
0
Therefore, the asymmetric protonation[7,20] was executed
in the presence of a chiral proton source (Table 4). THF
was used as an aprotic solvent instead of protic MeOH to
prevent proton transfer from the achiral protic solvent. The
use of chiral alcohol proton sources such as binaphthol
(BINOL) gave the α-amino acid in 32% yield with 8%ee
(Table 4, Entry 2). The enantioenriched amino acid was ac-
tually obtained with chiral amino acids, diamines, and their
trace
0
48
50
54
0
CH2Cl2 + H2O (δ =100 ppm)
MeOH
9
10[a]
11[a]
12
MeOH
MeOH (50 °C)
MeOH + TEMPO
[a] C4F9I (8 equiv.) and In (7 equiv.) were used.
The reaction of n-C4F9I with various dehydroamino es- hydrochloride salts (Table 4, Entries 3–7). The hydrochlo-
ters (1) was further investigated under the best reaction con- ride salt of the cyclic diamine 1,2-diaminocyclohexane
ditions (Table 3). Cbz-protected dehydroamino esters (1a (DACy) gave the amino ester product with 28%ee in 16%
and 1b) gave good yields. Boc and Teoc protection (1c and yield (Table 4, Entry 4). Acyclic diamine derivatives, the hy-
1d) gave lower yields. Free carboxylic acid 1e also under- drochloride salt of diphenylethylenediamine (DPEN),
went the reaction but in low yield. No reaction took place DPEN·2HCl, in particular gave the highest enantio-
with β-substituted dehydroamino ester 1f. The reactivity of selectivity (58%ee; Table 4, Entry 7).
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Eur. J. Org. Chem. 2010, 2461–2464

Direct Racemic Mixture Synthesis of Fluorinated Amino Acids
Table 4. Asymmetric protonation with chiral proton sources.
Conclusions
In conclusion, we have developed direct access to β-per-
fluoroalkyl α-amino acids through the In-mediated re-
ductive radical addition of perfluoroalkyl iodides to dehy-
droamino acids terminated by asymmetric protonation to
give products in up to 58%ee. The reaction can be further
extended to the direct racemic mixture synthesis by using a
single chiral HPLC column for simultaneous demix/
enantioseparation/identification to give the enantiopure
pairs of different lengths of β-perfluoroalkyl α-amino acids.
Entry
Chiral proton source
% Yield
%ee[a]
1
2
3
4
5
6
7
none
(R)-BINOL
()-proline
24
32
34
16
19
19
21
–
8
13
28
0
30
58
(R,R)-DACy·2HCl
(R,R)-DPENTf
(R,R)-DPEN
(R,R)-DPEN·2HCl
Experimental Section
[a] Determined by chiral HPLC (DAICEL AD-H) analysis.
Typical Experimental Procedure for the Direct “Racemic” Mixture
Synthesis (RMS) Terminated by Asymmetric Protonation: To a solu-
tion of dehydroamino ester 1a (94 mg, 0.4 mmol) in THF (6 mL)
was added In (powder, 184 mg, 1.6 mmol, 4 equiv.) and three kinds
of perfluoroalkyl iodides [CF3I (1.6 g, 8 mmol, 20 equiv.), n-C3F7I
(0.12 mL, 0.8 mmol, 2 equiv.), and n-C4F9I (0.14 mL 0.8 mmol,
2 equiv.)] at room temperature, and the reaction mixture was heated
at 50 °C. After stirring for 1 h at that temperature, the reaction
mixture was treated with the hydrochloride salt of diphenyl-
ethylenediamine (DPEN·2HCl; 114 mg, 0.4 mmol, 1 equiv.) at
room temperature for 1 h. The mixture was extracted with CH2Cl2,
and the extract was washed with brine, dried with Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified
by flash silica gel column chromatography to afford pure products
in 43% combined yield. Yield was determined by 1H NMR spec-
troscopy by using (CHCl2)2 as an internal standard. The mixture
thus obtained was separated into three enantiomer pairs of β-per-
fluoroalkyl α-amino esters by using a single chiral (DAICEL AD-
H) HPLC column as follows: HPLC analysis was performed with
a JASCO HPLC system (pump: PU-1580, gradient unit: LG-1580-
04, degasser: DG-1580-54, column oven: CO-1560, UV and CD
detector: CD-1595, auto sampler: AS-1555) by using a polysaccha-
ride-based chiral column (DAICEL CHIRALPAK® AD-H,
25 cmϫ4.6 mm i.d.) with a GL cart (0.5 cm ϫ4.6 mm i.d.) as a
guard column and a JASCO HPLC system [pump: PU-1580, gradi-
ent unit: LG-1580-04, degasser: DG-1580-54, column oven: CO-
1560, UV and CD detector: CD-995 (1595), auto sampler: AS-
1555]. Peak areas were calculated by JASCO-BORWIN as an auto-
matic integrator.
The RMS of fluorinated amino acids can thus be termin-
ated by asymmetric protonation[7,19] (Figure 1). The mix-
ture of three perfluoroalkyl iodides [RfI = CF3I (large ex-
cess because of volatility), n-C3F7I, and n-C4F9I] was
treated with dehydroamino ester 1a and then DPEN·2HCl
in the same pot to give a mixture of perfluoroalkylated ala-
nine derivatives in 43% combined yield. The separation of
the mixture into six pure enantiomers was then established.
All six enantiomers were baseline separated just by using a
single chiral column (DAICEL AD-H), without orthogonal
use of a fluorous column. Each amino ester was separated
and identified respectively as shown in the order of decreas-
ing lengths of the perfluoroalkyl substituents (Retention
times: n-C4F9 Ͻ n-C3F7 Ͻ CF3). The absolute configura-
tion of the enantiomers could be determined by CD or OR
detectors.[21] The one-pot radical addition/asymmetric pro-
tonation reaction and simultaneous demix/enantiosepa-
ration/identification thus solves the problems in solution-
phase combinatorial synthesis just by using a single chiral
column and six pure enantiomers were obtained, depending
on the lengths of the fluorinated amino acids.
Acknowledgments
This research was supported in part by a Sasagawa Scientific Re-
search Grant (No. 20-338) for T. T.
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T. Yajima, T. Tonoi, H. Nagano, Y. Tomita, K. Mikami
SHORT COMMUNICATION
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Published Online: March 18, 2010
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2461–2464