Catalytic route to the synthesis of optically active β,β- difluoroglutamic acid and β,β-difluoroproline derivatives

Article abstract of DOI:10.1021/jo049789c

β,β-Difluorinated amino acid derivatives were synthesized via Mg(0)-promoted defluorination of α-trifluoromethyl iminoester. Bromination of the difluoroenamine afforded the bromodifluoromethyl iminoester in good yield. Pd-catalyzed asymmetric hydrogenation of the bromodifluoromethyl iminoester and the subsequent transformations provided optically active β,α-difluoroglutamic acid and β,β-difluoroproline derivatives.

Full text of DOI:10.1021/jo049789c

tigation of new biological activities of fluorinated amino
acids,11 a more practical and general route to fluorinated
R-amino acids, particularly for their optical pure enan-
tiomers,12 is quite attractive. In 1995, Shi et al. reported
the divergent synthesis of racemic â,â-difluoroglutamic
acid and â,â-difluoroproline.13 Key features of their
pioneering work are follows: (i) the use of â,â-difluoro-
R-aminoesters as a common precursor, which were pre-
pared from trifluoropyruvate via reductive dechloroflu-
orination, Claisen rearrangement, and the subsequent
reductive amination and (ii) the application of oxidative
cleavage of C-C double bonds in fluorinated aminoesters,
which provided difluoroglutamic acid and difluoroproline
selectively.
Ca ta lytic Rou te to th e Syn th esis of
Op tica lly Active â,â-Diflu or oglu ta m ic Acid
a n d â,â-Diflu or op r olin e Der iva tives
Atsushi Suzuki, Masayuki Mae, Hideki Amii, and
Kenji Uneyama*
Department of Applied Chemistry, Faculty of Engineering,
Okayama University, 3-1-1 Tsushimanaka,
Okayama 700-8530, J apan
uneyamak@cc.okayama-u.ac.jp
Received February 6, 2004
Abstr a ct: â,â-Difluorinated amino acid derivatives were
synthesized via Mg(0)-promoted defluorination of R-trifluo-
romethyl iminoester. Bromination of the difluoroenamine
afforded the bromodifluoromethyl iminoester in good yield.
Pd-catalyzed asymmetric hydrogenation of the bromodifluo-
romethyl iminoester and the subsequent transformations
provided optically active â,â-difluoroglutamic acid and â,â-
difluoroproline derivatives.
Herein, we present an enantioselective synthesis of
â,â-difluoroglutamic acid derivatives (3) and â,â-difluo-
roproline derivatives (4) possessing general N- and
O-protecting groups by the use of the chiral common
precursor 2, which was prepared via the catalytic asym-
metric hydrogenation of bromodifluoromethylated imi-
noester 1 (Scheme 1).
Trifluoromethyl iminoester 514,15 underwent reductive
defluorination upon treatment with metallic magnesium
Among various organofluorine compounds, fluorinated
amino acids have been studied as potential enzyme
inhibitors and therapeutic agents.1-3 Recently, in amino
acid and peptide chemistry, amino acids possessing two
fluorine atoms at the â-carbon have been paid much
attention because they can act as potent inactivators of
certain enzymes, in particular, highly selective inhibitors
of pyridoxal phosphate-dependent enzymes via a suicide-
type mechanism, and can block certain important meta-
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10.1021/jo049789c CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/22/2004
5132
J . Org. Chem. 2004, 69, 5132-5134

SCHEME 1
(up to 91% ee) by employing fluorinated alcohols such as
2,2,2-trifluoroethanol (TFE) as a solvent. Thus, we exam-
ined asymmetric hydrogenation of bromodifluoromethyl
iminoester 1 catalyzed by a chiral palladium complex.
When iminoester 1 was subjected to a hydrogen pressure
in the presence of a small amount of Pd(OCOCF3)2 and
(R)-BINAP in TFE, the catalytic asymmetric hydrogena-
tion of 1 proceeded smoothly at room temperature to yield
aminoester (R)-2 in 88% ee. The absolute configuration
of (R)-2 was confirmed by its transformation to the known
(R)-11.22 Notably, the bromo functionality was compatible
with the present reaction conditions; the hydrogenolysis
of C-Br bonds in 1 and 2 did not occur. Subsequently,
the allylation of (R)-2, a versatile precursor of optically
active â,â-difluoroamino acids, was carried out via a
radical substitution reaction. Upon treatment with al-
lyltributyltin and a catalytic amount of AIBN as a radical
initiator, (R)-2 underwent radical allylation to afford
C-allylated aminoester (R)-7 in 56% yield with 87% ee
for two steps from bromoiminoester 1.
and trimethylsilyl chloride,16-19 leading to enaminoester
6. A gram-scale preparation of difluoroacrylate 6 (10
mmol scale) was executed under basic conditions, and the
selective defluorination proceeded smoothly at 0 °C to
afford 6 in 50% isolated yield (Scheme 2). Introduction
SCHEME 2
Using chiral aminoester (R)-7, we tried to synthesize
highly enantioenriched â,â-difluoroglutamic acid deriva-
tives. In previous work done by Shi et al., the synthesis
of racemic â,â-difluoroglutamic acid was accomplished via
hydrolysis of the corresponding ethyl esters under severe
conditions (refluxing in 6 N HCl). For the asymmetric
synthesis of amino acids, the choice of the N- and
O-protecting groups is of significant importance. We
sought to introduce general and easily removable pro-
tecting groups such as benzyl groups into the enantioen-
riched difluoro amino acids. Transesterification of ethyl
ester (R)-7 with benzyl alcohol using a catalytic amount
of 3-chloro-1-hydroxytetrabutyldistannoxane (CHTD)23
afforded the corresponding benzyl ester (R)-8 in high
yield (Scheme 3).
of a bromo group is considered to be of great advantage
to further transformations of 6, since chiral bromoester
2 is a versatile building block of enantioenriched â,â-
difluorinated amino acid. Enaminoester 6 was treated
with NBS to provide the corresponding bromodifluoro-
methyl iminoester 1 in excellent yield.
Until now, most of optically active â,â-difluoro-R-amino
acids have been mostly synthesized via diastereoselective
routes by the use of chiral auxiliaries but rarely done via
catalytic asymmetric routes, to our knowledge.20 Enan-
tioselective transformations of fluorinated R-iminoesters
are one of the useful methods for the asymmetric syn-
thesis of fluorinated R-amino acids. Recently, we reported
the Pd-catalyzed hydrogenation of R-trifluoromethyl imi-
noesters.21 Under a hydrogen pressure, a catalytic amount
of Pd(OCOCF3)2 and (R)-BINAP promoted the asym-
metric hydrogenation of trifluoromethylated iminoester
5 to afford the highly enantioenriched trifluoroalanine
derivative. Very interestingly, both the yield and ee of
this catalytic hydrogenation were dramatically improved
SCHEME 3 a
(16) A short account: Uneyama, K.; Amii, H. J . Fluorine Chem.
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Commun. 1999, 1323. (b) Amii, H.; Kobayashi, T.; Uneyama, K.
Synthesis 2000, 2001. (c) Amii, H.; Hatamoto, Y.; Seo, M.; Uneyama,
K. J . Org. Chem. 2001, 66, 7216. (d) Amii, H.; Kobayashi, T.; Terasawa,
H.; Uneyama, K. Org. Lett. 2001, 3, 3103. (e) Hata, H.; Kobayashi, T.;
Amii, H.; Uneyama, K.; Welch, J . T. Tetrahedron Lett. 2002, 43, 6099.
(18) (a) Uneyama K.; Kato T. Tetrahedron Lett. 1998, 39, 587. (b)
Mae, M.; Amii, H.; Uneyama, K. Tetrahedron Lett. 2000, 41, 7893. (c)
Mae, M.; Matsuura, M.; Amii, H.; Uneyama, K. Tetrahedron Lett. 2002,
43, 2069. (d) Kobayashi, T.; Nakagawa, T.; Amii, H.; Uneyama, K. Org.
Lett. 2003, 5, 4297. (e) Amii, H.; Ichihara, Y.; Nakagawa, T.; Kobayashi,
T.; Uneyama, K. Chem. Commun. 2003, 2902.
a
Reagents: (a) CHTD, BnOH, toluene. (b) (i) CAN, CH3CN; (ii)
Na2S2O3 then (Boc)2O, NaHCO3. (c) (i) CAN, CH3CN; (ii) Na2S2O3,
then Cbz-Cl, NaHCO3. (d) RuO2‚xH2O, 10% NaIO4 aq, AcOEt.
(19) (a) Prakash, G. K. S.; Hu, J .; Olah, G. A. J . Fluorine Chem.
2001, 112, 355. (b) Prakash, G. K. S.; Hu, J .; Alauddin, M. M. J .
Fluorine Chem. 2003, 121, 239.
(20) (a) Sakai, T.; Yan, F.; Uneyama, K. Synlett 1995, 753. (b) Sakai,
T.; Yan, F.; Kashino, S.; Uneyama, K. Tetrahedron 1996, 52, 233.
(21) Abe, H.; Amii, H.; Uneyama, K. Org. Lett. 2001, 3, 313.
(22) For (R)-12 (87% ee): [R]25D ) 21.8 (c 0.91, CHCl3). For (S)-1210g
(>95% ee): [R]25 ) -22.6 (c 0.62, CHCl3).
D
(23) (a) Otera, J .; Yano, T.; Okawa, R. Chem. Lett. 1985, 901. (b)
Otera, J .; Yano, T.; Okawa, R. Organometallics 1986, 5, 1167. (c) Otera,
J .; Dan-oh, N.; Nozaki, H. J . Org. Chem. 1991, 56, 5307.
J . Org. Chem, Vol. 69, No. 15, 2004 5133

SCHEME 5 a
Subsequently, the p-methoxyphenyl (PMP) group on
the amino nitrogen of (R)-8 was removed, and then tert-
butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz) groups
were introduced as common protecting groups of amino
nitrogen, to provide N-protected â,â-difluoroaminoesters
(R)-9a and (R)-9b, respectively. Fortunately, the optical
purity of N-Cbz derivative 9b increased by simple re-
crystallization, affording enantiomerically pure (R)-9b
(>99% ee).
Oxidative cleavage of C-C double bond in (R)-9a by
the use of RuO2‚H2O/NaIO4 was examined. However, the
desired product (R)-10a was not obtained selectively, but
a complex mixture was provided (Scheme 3). It can be
explained that there existed the competition of oxidation
of the terminal olefin moiety of 9a with that of the
benzylic carbon of the benzyl ester even at a low tem-
perature (-30 °C), because the benzylic position of 9a
was quite sensitive to the oxidative conditions.
a
Reagents: (a) (i) O3/O2, CH2Cl2; (ii) Me2S. (b) PPh3‚Cl2, DMF.
(c) H2 (1 atm), RhCl(PPh3)3, benzene.
Ozonolysis of N-protected â,â-difluoroamino esters
(R)-9 followed by the reductive treatment of the resulting
ozonide with Me2S afforded cyclic hemiaminal (R)-14 in
high yields (as a mixture of the diastereomers). When
benzyl ester (R)-14a was treated with dichlorotriph-
enylphosphorane, an elimination reaction took place to
afford olefin 15a in quantitative yield. Fortunately, the
purity of 15a was high enough for the next step. The
subsequent Rh(I)-catalyzed hydrogenation of olefin (R)-
15a proceeded smoothly to give the desired compound
(R)-4a , and N-(Boc)-protected difluoroproline was ob-
tained in high yield (83% from (R)-14a ). Moreover, by
the use of enantiomerically pure precursor (R)-9b (>99%
ee), N-(Cbz)-protected difluoroproline (R)-4b was ob-
tained in high optical purity (>99% ee).
Thus, to avoid the oxidation of the benzylic carbon,
ethyl ester (R)-7 (87% ee) was used for the oxidative
transformation (Scheme 4). At first, the N-p-methoxy-
SCHEME 4 a
In conclusion, we have demonstrated the enantiose-
lective divergent synthesis of N- and O-protected â,â-
difluoroglutamic acids (3) and â,â-difluoroprolines (4). A
Pd/BINAP/TFE system was found to be effective for the
catalytic asymmetric hydrogenation of bromodifluoro-
methylated iminoesters 1, providing aminoesters 2 (88%
ee), which served as general precursors of enantioen-
riched â,â-difluorinated R-amino acids. Furthermore,
N-(Cbz)-protected difluoroproline (4b) was obtained in
high optical purity (>99% ee) via simple recrystallization.
We believe that these results make a great contribution
toward further potential biological and chemical applica-
tions.
a
Reagents: (a) (i) CAN, CH3CN; (ii) Na2S2O3, then (Boc)2O,
NaHCO3. (b) RuO2‚xH2O, 10% NaIO4 aq, AcOEt. (c) BnBr, CsF,
DMF. (d) CHTD, BnOH. (e) TFA, CH2Cl2. (f) Cbz-Cl, NaHCO3,
1,4-dioxane-H2O.
phenyl group of ethyl ester (R)-7 was removed; then, a
t-butoxycarbonyl (Boc) group was introduced to the
substrate as an N-protecting group, and the desired
N-protected-â,â-difluoroamino ester (R)-11 was afforded
in 84% yield. Then, under the oxidative condition (RuO2‚
H2O/NaIO4), ethyl ester (R)-11 was converted to the
desired product â,â-difluoroglutamic acid derivative (R)-
12 in 83% yield. CsF-mediated esterification24 to the
γ-carboxyl group of (R)-12 proceeded smoothly, and the
desired dibenzyl ester (R)-13 was obtained without any
loss of enantiomeric excess. At last, the transesterifica-
tion reaction by the use of CHTD smoothly proceeded,
affording the final target compound, enantioenriched N-
and O-protected difluoroglutamic acid (R)-3a in good
yield. After the deprotection-protection sequence, a Cbz
group was introduced as an alternative N-protecting
group to afford N-Cbz derivative (R)-3b in good yield.
The next target was the synthesis of optically pure â,â-
difluoroproline derivatives 4 by the use of the chiral
common precursors 9 (Scheme 5).
Ack n ow led gm en t. This work has been supported
by the Ministry of Education, Culture, Sports, Science
and Technology of J apan (Grant-in-Aid for Scientific
Research (B), No. 13555254, Grant-in-Aid for Young
Scientists (B), No. 14750684, and Grant-in-Aid for
Scientific Research on Priority Areas (“Reaction Control
of Dynamic Complexes”), No. 16033621). H.A. received
a research grant from Okayama Prefecture. We also
thank the SC-NMR laboratory of Okayama University
for 19F NMR analysis.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and compound characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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5134 J . Org. Chem., Vol. 69, No. 15, 2004
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