At the same time, organofluorine compounds have become
increasingly more important in the past few years because
the presence of fluorine atoms in a potentially bioactive
molecule can dramatically change not only its physical but
previous experience in the synthesis of R-alkyl â-amino acid
1
1
derivatives, we report here a highly diastereo- and enan-
tioselective approach to fluorinated syn-R-alkyl γ-amino
alcohols by means of an indirect Mannich-type reaction of
fluorinated aldimines and aliphatic aldehydes catalyzed by
6,7
also its chemical properties.
1
3
In recent years, several helpful approaches to R-alkyl
â-amino acids1 have been reported, but surprisingly little
work has been done on R-alkyl â-(fluoroalkyl) â-amino
proline (Scheme 2).
e,8
9
acids. In fact, only two main strategies have been developed
Scheme 2
thus far for the synthesis of derivatives of these compounds
in a chiral, nonracemic fashion (Scheme 1). Thus, Solo-
Scheme 1
We first decided to explore the feasibility of using
fluorinated aldehydes as substrates for proline catalysis of
three-component, one-pot asymmetric Mannich-type reac-
tions. Since these compounds lack enolizable hydrogens, they
do not undergo self-aldol condensations, making their
4
behavior similar to that of aromatic aldehydes. However,
shonok10 described in 1998 a chemoenzymatic two-step
approach to R-alkyl â-fluoroalkyl â-amino acids that relies
on a diastereoselective biomimetic transamination [proton
shift reaction, or PSR] of fluorinated R-alkyl â-keto car-
boxylic esters followed by enantioselective biocatalytic
resolution in the presence of penicillin acylase. More
recently, our group published an effective and highly
diastereoselective route to enantiopure syn-R-alkyl-γ-
fluorinated â-amino acid derivatives based on a chemo- and
diastereoselective reduction of chiral fluorinated â-enamino
esters derived from (-)-8-phenylmenthol.11
the results from our first reaction, which involved propanal,
p-anisidine, and trifluoroacetaldehyde ethyl hemiacetal at
-20 °C in N-methylpyrrolidone (NMP) as a solvent and in
the presence of L-proline (20 mol %) as a catalyst, followed
by NaBH reduction of the initially formed â-amino alde-
4
1
4
hyde, were disappointing, as the reaction did not afford
the desired fluorinated γ-amino alcohol. Instead, we were
only able to isolate byproducts corresponding to the self-
4
e
Mannich reaction of propanal.
This negative result prompted us to modify our strategy.
Since fluorinated aldehydes are stable as hydrates or hemi-
acetals, losing their characteristic reactivity in those forms,
we decided to try an indirect version of the condensation
described above, this time using a preformed fluorinated
aldimine 1. Indeed, when fluorinated aldimines 1 and
propanal were initially reacted in the same conditions as those
In connection with our ongoing investigations into the
development of new routes to the synthesis of organofluorine
12
nitrogen-containing compounds, and on the basis of our
(
5) (a) Hajos, Z. G.; Parrish, D. R. Asymmetric Synthesis of Optically
ActiVe Polycyclic Organic Compounds. German Patent DE 2102623, July
9, 1971. (b) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed.
Engl. 1971, 10, 496-497.
6) (a) Organo-Fluorine Compounds in Houben-Weyl Methods of
4f
used by Hayashi and co-workers [NMP as a solvent at -20
°C in the presence of L-proline (20 mol %)], followed by
2
(
4
the reduction of the amino aldehyde with NaBH in MeOH
Organic Chemistry, Workbench Edition E10a-c; Georg Thieme Verlag:
Sttutgart, 2000. (b) Fluorine-Containing Amino Acids: Synthesis and
Properties; Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley: Chichester,
UK, 1995.
at 0 °C, the desired syn-γ-amino alcohol 2 was obtained,
albeit in only 17% yield, with a large quantity of starting
material left unreacted.
(7) The importance of organofluorinated compounds, and especially of
their synthesis in chiral form, has been described in the very recent work
of McMillan, Jørgensen, Barbas III, and Enders. See: (a) Beeson, T. D.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826-8828. (b) Marigo,
M.; Fielenbach, D.; Braunton, A.; Kjœrsgaard, A.; Jørgensen, R. A. Angew.
Chem., Int. Ed. 2005, 44, 3707-3706. (c) Steiner, D. D.; Mase, N.; Barbas,
C. F., III. Angew. Chem., Int. Ed. 2005, 44, 3706-3710. (d) Enders, D.;
H u¨ ttl, M. R. Synlett 2005, 991-993.
We then attempted to optimize the reaction conditions in
order to improve the chemical yield. Thus, when the reaction
(12) (a) Fustero, S.; Piera, J.; Sanz-Cervera, J. F.; Catalan, S.; Ramirez
de Arellano, C. Org. Lett. 2004, 6, 1417-1420. (b) Fustero, S.; Bartolome,
A.; Sanz-Cervera, J. F.; Sanchez-Rosello, M.; Soler, J. G.; Ramirez de
Arellano, C.; Fuentes, A. S. Org. Lett. 2003, 5, 2523-2526. (c) Fustero,
S.; Salavert, E.; Sanz-Cervera, J. F.; Piera, J.; Asensio, A. Chem. Commun.
2003, 844-845. (d) Fustero, S.; Soler, J. G.; Bartolome, A.; Rosello, M. S.
Org. Lett. 2003, 5, 2707-2710. (e) Sani, M.; Bruch e´ , L.; Chiva, G.; Fustero,
S.; Piera, J.; Volonterio, A.; Zanda, M. Angew. Chem., Int. Ed. 2003, 42,
2060-2063.
(
8) Reviews: (a) Cole, D. C. Tetrahedron 1994, 50, 9517-9582. (b)
Juaristi, E.; Quintana, D.; Escalante, J. Aldrichimica Acta 1994, 27, 3-11.
9) For the racemic synthesis of R-alkyl â-(fluoroalkyl) â-amino acids,
see: (a) Kaneko, S.; Yamazaki, T.; Kitazume, T. J. Org. Chem. 1993, 58,
(
2
2
2
302-2312. (b) Takaya, J.; Kagoshima, H.; Akiyama, R. Org. Lett. 2000,
, 1577-1579. (c) Sergeeva, N. N.; Golubev, A. S.; Burger, K. Synthesis
001, 281-285.
(13) Although proline has been recently shown to catalyze the addition
of acetone to a few fluorinated aldimines, the yields obtained were generally
low and the method was restricted to the use of acetone as both solvent
and reagent; other ketones failed to react under these conditions. See:
Funabiki, K.; Nagamori, M.; Goushi, S.; Matsui, M. Chem. Commun. 2004,
1928-1929.
(
10) Soloshonok, V.; Soloshonok, I.; Kukhar, V. P.; Svedas, V. K. J.
Org. Chem. 1998, 63, 1878-1884.
(11) (a) Fustero, S.; Pina, B.; Garc ´ı a de la Torre, M.; Navarro, A.;
Arellano, C. R.; Sim o´ n, A. Org. Lett. 1999, 1, 977-980. (b) Fustero, S.;
Pina, B.; Salavert, E.; Navarro, A.; Arellano, C. R.; Sim o´ n, A. J. Org. Chem.
2
002, 67, 4667-4679.
(14) C o´ rdova, A. Synlett 2003, 1651-1654. See also refs 4f and 4j.
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Org. Lett., Vol. 7, No. 16, 2005