strategy, since the presence of a fluorine atom often induces
significant changes in the physical properties, biological
activities, and metabolic profiles of the resulting peptides.7
Although both acyclic and cyclic quaternary R-amino acids
have been frequent synthetic targets,2c,d few syntheses of their
fluorinated counterparts are known. Even rarer are examples
of the preparation of quaternary cyclic fluorinated R-amino
acids, and of the few there are, most deal with fluorinated
1-aminocyclopropane carboxylic acids.8 To date, only a
single example has been reported of the preparation of
racemic heterocyclic quaternary R-amino acids with a CF3
group by means of a ring-closing metathesis reaction
(RCM).9 Herein we describe a new synthetic strategy that
provides an entry to enantiomerically pure â,â-difluorinated
cyclic quaternary R-amino acids 1 and in which a RCM
constitutes the key step10 (Scheme 1, retrosynthetic analysis).
alcohols in the presence of a catalytic amount of Pd2(dba)3‚
CHCl3 complex to afford imino esters 5 in moderate yields
(Table 1).14
Table 1. Synthesis of Imino Esters 5
entry
3
R1
R2
Et
Bn
TMSEc
Bn
5 (yield)a
1
2
3
4
5
6
3a
3a
3a
3b
3c
3c
PMPb
PMPb
PMPb
5a (55)
5b (60)
5c (52)
5d (70)
5e (50)
5f (51)
Scheme 1. Retrosynthetic Analysis
(S)-PhCH(Me)
(R)-phegly-OMed
(R)-phegly-OMed
Bn
TMSEc
a Yield of isolated product, %. b PMP ) p-MeOC6H4. c TMSE )
2-trimethylsilylethyl. d (R)-phegly-OMe ) (R)-PhCH(CH2OMe).
In our approach, the â,â-difluorinated cyclic R-amino acid
1 was disconnected at the C4-C5 double bond by means of
a RCM reaction. In turn, the corresponding precursor 6 was
disconnected at the C1-C6 bond through an allylation
reaction on imino ester 5 with a suitable organometallic
species (Scheme 1). Finally, imino ester 5 is synthesized from
2,2-difluoro-4-pentenoic acid 2.11
R-Imino esters 5 were prepared with the method described
by Uneyama and co-workers.12 Thus, 2,2-difluoro-4-pen-
tenoic acid 2 was initially transformed into the corresponding
imidoyl chlorides 3a-c,13 which were then converted into
imydoyl iodides 4a-c by reacting them with NaI in dry
acetone. These reactive intermediates were treated without
further purification with carbon monoxide and several
With imino esters 5 in hand, the next step was the
chemoselective allylation of the imino group in the imino
ester (initially in its racemic form in substrates 5a-c).
Several authors have previously carried out this type of
transformation using organometallic (Mg, Li, Zn) deriva-
tives.9,15 The best preliminary results with achiral susbstrates
5a-c were obtained through the use of allylzinc bromides,
which caused the addition to take place exclusively at the
iminic carbon in 10 min at -40 °C, thus furnishing the
desired racemic R-amino esters 6a-d in almost quantitative
yield.16 Compounds 6a-d were then subjected to RCM
through treatment with second generation Grubbs catalyst
(IHMes)(PCy3)Cl2RudCHPh (8)17 in refluxing dichlo-
romethane to furnish cyclic R-amino esters 7a-d in excellent
yields (Table 2, entries 1-4).
(6) Kowalczyk, W.; Prahl, A.; Derdowska, I.; Dawidowska, J.; Slaninova´,
J.; Lammek, B. J. Med. Chem. 2004, 47, 6020-6024.
(7) (a) Fluorine-Containing Amino Acids: Synthesis and Properties;
Kukhar, V. P., Soloshonok, V. A., Eds.; J. Wiley and Sons: New York,
1995. (b) Biomedical Aspects of Fluorine Chemistry; Filler, R., Kobayashi,
Y., Eds.; Elsevier Biomedical: Amsterdam, 1982.
Finally, we carried out an example of the removal of the
amino acid protecting groups on compound 7c. Thus,
oxidative treatment of compound 7c with ceric ammonium
(8) (a) Kirihara, M.; Takuwa, T.; Kawasaki, M.; Kakuda, H.; Hirokami,
S. I.; Takahata, H. Chem. Lett. 1999, 405-406. (b) Katagiri, T.; Irie, M.;
Uneyama, K. Org. Lett. 2000, 2, 2423-2425.
(14) The similarity of the retention time between dibenzalacetone
(palladium ligand) and the final imino esters 5 made the purification of
these compounds difficult, thus decreasing the yield of isolated products.
(15) See, for example: (a) Osipov, S. N.; Golubev, A. S.; Sewald, N.;
Michel, T.; Kolomiets, A. F.; Fokin, A. V.; Burger, K. J. Org. Chem. 1996,
61, 7521-7528. (b) Amii, H.; Kishikawa, Y.; Kageyama, K.; Uneyama,
K. J. Org. Chem. 2000, 65, 3404-3408. (c) Asensio, A.; Bravo, P.;
Crucianelli, M.; Farina, A.; Fustero, S.; Garc´ıa Soler, J.; Meille, S. V.;
Panzeri, W.; Viani, F.; Volonterio, A.; Zanda, M. Eur. J. Org. Chem. 2001,
1449-1458. (d) Hanessian, S.; Yang, R. Y. Tetrahedron Lett. 1996, 37,
8997-8990.
(9) (a) Osipov, S. N.; Bruneau, C.; Picquet, M.; Kolomiets, A. F.;
Dixneuf, P. H. Chem. Commun. 1998, 2053-2054. (b) Osipov, S. N.;
Artyushin, O. I.; Kolomiets, A. F.; Bruneau, C.; Picquet, M.; Dixneuf, P.
H. Eur. J. Org. Chem. 2001, 3891-3897.
(10) Grubbs, R. H. In Handbook of Metathesis; Wiley-VCH Verlag:
Weinheim, 2003; Vols. 1-3.
(11) Lang, R. W.; Greuter, H.; Romann, A. J. Tetrahedron Lett. 1988,
29, 3291-3294.
(12) Amii, H.; Kishikawa, Y.; Kageyama, K.; Uneyama, K. J. Org. Chem.
2000, 65, 3404-3408.
(16) The allyl zinc halide must be freshly prepared and used immediately
in order to obtain the results indicated above.
(13) (a) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.; Uneyama,
K. J. Org. Chem. 1993, 58, 32-36. (b) Fustero, S.; Navarro, A.; Pina, B.;
Garc´ıa Soler, J.; Bartolome´, A.; Asensio, A.; Simo´n, A.; Bravo, P.; Fronza,
G.; Volonterio, A.; Zanda, M. Org. Lett. 2001, 3, 2621-2624.
(17) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956. (b) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751-
1753. (c) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J.
Am. Chem. Soc. 2000, 122, 3783-3784.
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Org. Lett., Vol. 8, No. 18, 2006