Novel synthesis of cyclic α-amino acid esters via ene reaction and ruthenium-catalyzed ring rearrangement

Article abstract of DOI:10.1055/s-2001-13362

New fluorinated unsaturated cyclic α-amino acid esters were obtained by ene reaction of methylenecycloalkanes with electrophilic imines (CF₃)(MeO₂C)C=N-PG, followed by ruthenium-catalyzed ring rearrangement involving mixed ROM-RCM me

Full text of DOI:10.1055/s-2001-13362

LETTER
621
Novel Synthesis of Cyclic -Amino Acid Esters via Ene Reaction and
Ruthenium-catalyzed Ring Rearrangement
Sergey N. Osipov,a* Natalia M. Kobelíkova,a Gregory T. Shchetnikov,a Alexey F. Kolomiets,a Christian Bruneau,b
Pierre H. Dixneufb*
a A. N. Nesmeyanov Institute of Organoelement Compounds, Vavilov st. 28, 117813 Moscow, GSP-1, Russia
Fax +7 095 135 5085; E-mail: osipov@ineos.ac.ru
b Institut de chimie de Rennes, UMR 6509 CNRS-Université de Rennes, Campus de Beaulieu, 35042 Rennes, France
Fax +33 (0)2 99 28 69 39; E-mail: pierre.dixneuf@univ-rennes1.fr
Received 24 January 2001
The ene reaction with imines has been performed in the
Abstract: New fluorinated unsaturated cyclic -amino acid esters
presence of Lewis acid and metal catalysts9 in order to in-
were obtained by ene reaction of methylenecycloalkanes with elec-
trophilic imines (CF3)(MeO2C)C=N-PG, followed by ruthenium-
catalyzed ring rearrangement involving mixed ROM-RCM met-
crease the electrophilicity of the imine carbon atom. The
highly electrophilic -CF3-substituted imines of type 1,10
athesis.
by contrast, readily react in the absence of catalysts with
methylenecyclopentane and methylenecyclohexane to se-
lectively give the ene reaction product, the fluorinated un-
saturated -amino esters 2a-c and 3a-c in 68-98% yields
(Scheme 2). The reaction takes place at room temperature
for N-protecting groups of the type PG = SO2R, whereas
the use of the Boc protecting group requires heating at 90-
100 °C.
Key words: fluorinated amino acids, cyclic amino esters, ene reac-
tion, ROM-RCM metathesis
The ring closing metathesis reaction (RCM) has become
an important synthetic tool, due to the development of the
well-defined Schrock’s molybdenum1 and Grubbs’
ruthenium2 catalysts, which are able to tolerate most func-
tional groups and are very efficient for the selective syn-
thesis of a variety of carbo- and heterocycles.3 These
compounds were shown to catalyze ring opening metathe-
sis (ROM),4 which can be combined with cross metathe-
sis.4-6 To our knowledge, no application of combined
ROM-RCM reactions has been described for the prepara-
tion of fluorine containing cyclic -amino acid deriva-
tives, despite the special interest of -fluorinated -amino
acids, which can function as highly selective and potent
inhibitors of pyridoxal phosphate-dependent enzymes.7,8
The development of straightforward methods for the syn-
thesis of -fluorinated -amino acid derivatives thus re-
mains of current interest especially via simple catalytic
processes.
n = 0: 2a (98%), 2b (85%), 2c (83%)
n = 1: 3a (68%), 3b (79%), 3c (71%)
Scheme 2 PG = SO2Me (a); SO2Ph (b); Boc (c)
In order to perform the alkene metathesis reaction, an allyl
group was attached to the nitrogen atom of the amino es-
ters. The N-allylated derivatives 4, 5 were obtained in 49-
We now report a novel synthesis of 2-CF3-4-alkenyl cy- 68% yields on deprotonation of 2, 3 with NaH in DMF
clic amino esters based on two successive reactions: the and subsequent alkylation with allyl bromide (Scheme
uncatalyzed ene reaction of methylenecycloalkanes with 3).11
electrophilic trifluoromethylated imines, followed by ru-
thenium-catalyzed mixed ROM-RCM reactions leading
to ring rearrangement of the resulting cyclopentene or cy-
clohexene groups, which can potentially be applied to
most ene reaction products (Scheme 1).
Scheme 3 4a-c (n = 0); 5a-c (n = 1)
Alkene metathesis of the 5-membered ring containing de-
rivatives 4a-c was attempted with 10 mol% of the Grubbs’
2
catalyst Ru=CHPh(Cl)2(PCy3)2 in dichloromethane. Af-
ter 6-8 hours of stirring at room temperature the reaction
yielded the ROM-RCM rearranged products, the cyclic
Scheme 1
Synlett 2001 No. 5, 621–622 ISSN 0936-5214 © Thieme Stuttgart · New York

622
S. N. Osipov et al.
LETTER
amino esters 6a-c in 77-85% yields11 (Scheme 4). Analo-
gously, the cyclohexene derivatives 5a-c with the catalyt-
References and Notes
(1) Schrock, R.R.; Murdzek, J.S.; Bazan, G.C.; Robbins, J.;
DiMare, M.; O’Regan, M.J. J. Am. Chem. Soc. 1990, 112,
3875; Schrock, R. R. In Alkene Metathesis in Organic
Synthesis - Topics in Organometallic Chemistry, Springer:
Berlin, 1998, pp 1-36.
ic
ROM-RCM
action
of
10
mol%
of
Ru=CHPh(Cl)2(PCy3)2 led to the derivatives 7a-c in 74-
86% yield11. Thus, this reaction allows the straightfor-
ward formation of fluorinated, unsaturated 6-membered
cyclic -amino esters with a terminal alkene chain of vari-
able length. It demonstrates that the formation of the 6-
membered amino ester cycle is the driving force of the
ROM-RCM reaction.
(2) Schwab, P.; France, M.B.; Ziller, J.W.; Grubbs, R.H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039.
(3) Hashmi, A.S.K. J. Prakt. Chem. 1997, 339, 195; Schmalz,
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(8) Kolonitsh, J.; Perkins, L.M.; Patchett, A.A.; Doldouras, G.A.;
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Scheme 4 Ru cat.: Ru=CHPh(Cl)2(PCy3)2
-CF3 Cyclic amino esters can be obtained via classical (10) Osipov, S.N.; Chkanikov, N.D.; Kolomiets, A.F.; Fokin, A.V.
ring closing metathesis of dienes.12 However, the present
method opens new possibilities of structural modifica-
tions of the amino esters: (i) the ring size is controlled by
the length of the alkene chain introduced on the nitrogen
atom and (ii) the resulting pendent chain length in 6-7 is
controlled by the ring size of the methylenecycloalkane
initially involved in the ene reaction.
Bull. Acad. Sci. USSR, Chem. Sect. (Eng.) 1986, 1256; Burger,
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(11) Selected data for 4c: 1.40 (s, 9H, t-Bu), 1.79 (pent, JHH 7.2 Hz,
2H, CH2), 2.17 (m, 4H, 2 CH2), 2.92 (s, 2H, CH2), 3.71 (s, 3H,
OMe), 3.76 and 4.12 (m, 2H, NCH2), 5.15 (d, JHH 10.4,
1H, =CH2), 5.29 (d, JHH 17.2, 1H, =CH2), 5.52 (s, 1H, =CH),
5.86 (m, 1H, =CH); F(CDCl3) -70.53 (s, 3F, CF3). For 5b:
1.43 (m, 4H, 2 CH2), 1.88 (m, 4H, 2 CH2), 2.62 (d, JAB 13.2
Hz, 1H, CH2), 2.83 (d, JAB 13.2 Hz, 1H, CH2), 3.82 (s, 3H,
OMe), 3.90 (d, JAB 18.2 Hz, 1H, NCH2), 4.02 (d, JAB 18.2 Hz,
1H, NCH2), 4.79 (d, JHH 10.4, 1H, =CH2), 4.90 (d, JHH 17.2,
1H, =CH2), 5.36 (m, 1H, =CH), 5.48 (s, 1H, =CH), 7.45-7.91
(m, Ph); F(CDCl3) -68.49 (s, 3F, CF3); For 6a: H(CDCl3)
1.55 (m, 2H, CH2), 2.06 (m, 4H, 2 CH2), 2.58 (d, JAB 16.7 Hz,
1H, CH2), 2.79 (d, JAB 16.7 Hz, 1H, CH2), 3.03 (s, 3H, SMe),
3.86 (s, 3H, OMe), 3.95 (m, 2H, NCH2), 5.01 (m, 2H, =CH2),
5.61 (m, 1H, =CH), 5.80 (m, 1H, =CH); F(CDCl3) -70.99 (s,
3F, CF3); For 7c: H(CDCl3) 1.18 (s, 9H, CMe3), 1.47 (m, 4H,
2 CH2), 2.01 (m, 4H, 2 CH2), 2.50 (d, JAB 18.0 Hz, 1H, CH2),
2.69 (d, JAB 18.0 Hz, 1H, CH2), 3.79 (s, 3H, OMe), 3.89 (m,
2H, NCH2), 4.91 (m, 2H, =CH2), 5.08 (m, 1H, =CH), 5.73 (m,
1H, =CH); F(CDCl3) -69.49 (s, 3F, CF3)
In summary, we have found a novel pathway to 6-mem-
bered heterocycles with endocyclic double bond and pen-
dent terminal alkene chain. This method allowed us to
develop an effective access to novel -CF3-containing
amino esters based on ruthenium-catalyzed ROM-RCM
reaction. The presence of the pendent chain, whose length
can be modulated, offers potential for functionalization
and copolymerisation.
Acknowledgement
The authors thank the European Union INTAS programm 97-1874
and the COST programm D12/0025/99 for support.
(12) Osipov, S.N.; Bruneau, C.; Picquet, M.; Kolomiets, A.F.;
Dixneuf, P.H. Chem. Commun. 1998, 2053.
Article Identifier:
1437-2096,E;2001,0,05,0621,0622,ftx,en;G01201ST.pdf
Synlett 2001, No. 5, 621–622 ISSN 0936-5214 © Thieme Stuttgart · New York