Tandem catalytic carbene addition/bicyclization of enynes. One-step synthesis of fluorinated bicyclic amino esters by ruthenium catalysis

Article abstract of DOI:10.1021/ol051393f

(Chemical Equation Presented) The reaction of diazo compounds with enynes, containing a fluorinated amino acid moiety, in the presence of the precatalyst Cp*(Cl)Ru(COD) leads to fluorinated alkenyl bicyclo[3.1.0]hexane and [4.1.0]heptane amino acid deriva

Full text of DOI:10.1021/ol051393f

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3741-3743
Tandem Catalytic Carbene Addition/
Bicyclization of Enynes. One-Step
Synthesis of Fluorinated Bicyclic Amino
Esters by Ruthenium Catalysis
Matthieu Eckert,† Florian Monnier,† Grigorii T. Shchetnikov,‡ Igor D. Titanyuk,‡
Serguej N. Osipov,‡ Loıc Toupet,§ Sylvie De´rien,† and Pierre H. Dixneuf*,†
1
Institut de Chimie de Rennes, UMR 6509 CNRS-UniVersite´ de Rennes 1, Campus de
Beaulieu, 35042 Rennes Cedex, France, A.N. NesmeyanoV Institute of Organoelement
Compounds, Russian Academy of Sciences (INEOS), VaViloV, st. 28, Moscow 119991,
Russia, and Groupe Matie`re Condense´e et Mate´riaux, UMR 6626 CNRS-UniVersite´ de
Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France
pierre.dixneuf@uniV-rennes1.fr
Received June 15, 2005
ABSTRACT
The reaction of diazo compounds with enynes, containing a fluorinated amino acid moiety, in the presence of the precatalyst Cp*(Cl)Ru(COD)
leads to fluorinated alkenyl bicyclo[3.1.0]hexane and [4.1.0]heptane amino acid derivatives. It is remarkable that the catalyst, in situ generated
from ruthenium complex and diazo compound, completely inhibits the ring closing metathesis of enyne to the profit of tandem alkenylation/
cyclopropanation with high stereoselectivity. The study shows that the Cp*(Cl)Ru moiety in ruthenacyclobutane favors reductive elimination
versus expected alkene metathesis.
Enynes play an important role in complex molecules
synthesis as they are the object of controlled metal-catalyzed
skeleton rearrangements leading to higher value cyclic
functional products.1 Nonconjugated enynes are suitable
substrates for the catalytic Pauson-Khand reaction,2 and they
are selectively transformed into conjugated alkenylcyclo-
alkenes using alkene metathesis catalysts.3 Recently,
platinum(II) and gold(I) catalysts have promoted the elec-
trophilic rearrangement of enynes into bicyclo[4.1.0]heptene
derivatives4a-c and of hydroxylated 1,5-enynes into bicyclic
ketones.4d Consequently, the enyne structure has gained the
potential to open the route to heterobicyclic compounds via
catalysis, including amino acid derivatives.
The incorporation of cyclic R-amino acids, bringing a
conformational restriction into peptides, can be an important
tool in drug discovery processes.5 Tyrosine has been suc-
cessfully replaced by a conformationally constrained bicyclic
† Institut de Chimie de Rennes, CNRS-Universite´ de Rennes 1.
‡ Russian Academy of Sciences.
§ Groupe Matie`re Condense´e et Mate´riaux, CNRS-Universite´ de
Rennes 1.
(1) (a) Bruneau, C. Angew. Chem., Int. Ed. 2005, 44, 2328. (b) Lloyd-
Jones, G. C. Org. Biomol. Chem. 2003, 1, 215. (c) Aubert, C.; Buisine, O.;
Malacria, M. Chem. ReV. 2002, 102, 813. (d) Mendez, M.; Mamane, V.;
Fuˆrstner, A. Chemtracts: Org. Chem. 2003, 16, 397.
(2) (a) Morimoto, T.; Chatani, N.; Fukumoto, Y.; Murai, S. J. Org. Chem.
1997, 62, 3762. (b) Kondo, T.; Suzuki, N.; Okada, T.; Mitsudo, T. J. Am.
Chem. Soc. 1997, 119, 6187. (c) Tang, Y.; Deng, L.; Zhang, Y.; Dong, G.;
Chen, J.; Yang, Z. Org. Lett. 2005, 7, 1657.
(3) (a) Kinoshita A.; Mori, M. Synlett 1994, 1020. (b) Mori, M. J. Mol.
Catal. A: Chem. 2004, 213, 73.
(4) (a) Fu¨rstner, A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc. 2001, 123,
11863. (b) Nieto-Oberhuber, C.; Paz Mun˜oz, M.; Bun˜uel, E.; Nevado, C.;
Ca´rdenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 2402.
(c) Mainetti, E.; Mourie`s, V.; Fensterbank, L.; Malacria, M.; Marco-
Contelles, J. Angew. Chem., Int. Ed. 2002, 41, 2132. (d) Mamane, V.; Gress,
T.; Krause, H.; Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 8654.
10.1021/ol051393f CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/16/2005

amino acid analogue in protein kinase.6 The evaluation of
strained bicyclic amino acids into peptides, and especially
of stabilizing fluorinated analogues, has not been performed
yet, likely due to the lack of straightforward method of
access.7
We now report a simple synthesis of fluorinated bicyclo-
[3.1.0]hexane and [4.1.0]heptane amino esters by ruthenium-
catalyzed tandem addition of diazoalkane/bicyclization of
fluorinated enynes under very mild conditions. We show that
the in situ generated alkylidene-ruthenium catalyst
[Cp*(Cl)RudCH-R] completely inhibits (a) the ring closing
metathesis of enyne to the profit of (b) tandem alkenylation/
cyclopropanation with high stereoselectivity (eq 1).
Under similar conditions, the 1,6-enynes 3b and 3c react
with N2CHSiMe3 in ether to give the diastereoisomers 5b
(60%) and 5c (59%) with the bicyclo[3.1.0]hexane structure
with the Z-configuration of the alkenyl group (eq 3). In that
case, the reaction is very fast with respect to that leading to
the derivatives 4, as for instance the reaction of 3b at room
1
temperature was completed in 10 min to give 5b. H NMR
studies showed that the major diastereoisomer contains the
trans-CO2Me and Z-Me3SiCHdCH groups. The X-ray
structure of the minor diastereoisomer of 5c confirmed the
cis-relative positions of these groups.11
The transformation of mixed propargyl allyl ethers and
amides into bicyclo[3.1.0]hexane derivatives was shown via
ruthenium-catalyzed reaction with diazoalkanes to take place
at 60 °C for 4-5 h.8 We have found now that when the
diazoalkane was produced in ether rather than in hexane,
the catalytic transformation of allyl propargyl tosylamide was
dramatically accelerated and could be completed at room
temperature, under conditions tolerating classical amino
acid protecting groups. Then, the new fluorinated enynes
2-3 have been prepared from the protected imines
CF3C(dNPG)CO2Me 19 by nucleophilic addition of allyl or
vinylmagnesium bromide followed by reaction with prop-
argyl bromide. The 1,7-enynes 2a-c (1 mmol) were reacted
with 1.15 equiv of N2CHSiMe3 in diethyl ether and 5
mol % of the precatalyst Cp*(Cl)Ru(COD) (I) at room
temperature for 3-4 h until complete conversion of 2 to the
amino esters 4 containing the bicyclo[4.1.0]heptane struc-
ture.10 These compounds were isolated in 68 (4a), 64 (4b),
and 73% (4c) yield, respectively (eq 2). Each of them
contained both diastereoisomers that have been separated
using chromatography on silica gel. Each diastereoisomer
shows a Z-configuration for the CHdCHSiMe3 group.
To study the general access to bicyclo[4.1.0]heptane
structures, enyne 6, with opposite positions of propargyl and
allyl groups on the nitrogen and carbon atoms with respect
to 2c, was synthesized and reacted with N2CHSiMe3 in the
presence of 5 mol % of catalyst I. The reaction under the
initial conditions8 (dioxane, 60 °C) afforded the bicyclo-
[4.1.0]heptane amino ester 7 isolated in only 35% yield
(eq 4).
The catalytic transformations of enynes 3 with ethyl
diazoacetate required higher temperature and were performed
in dioxane at 100 °C for 4 h. 3b and 3c led to the bicyclo-
[3.1.0]hexane amino esters 8b,c (eq 5). These compounds
possess the relative trans positions of the CO2Me and the
Me3SiCHdCH groups as for 5b and 5c, but they contain an
E-CHdCHCO2Et side chain, probably due to thermal factors
as the reaction takes place at about 100 °C.
(5) (a) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32,
1244. (b) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699.
(6) Donella-Deana, A.; Ruzza, P.; Cesaro, L.; Brunati, A. M.; Calderan,
A.; Borin, G.; Pinna, L. A. FEBS Lett. 2002, 523, 48.
(7) For examples of bicylic amino acid derivatives via cyclopropanation,
see: Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV.
2003, 103, 977.
(8) Monnier, F.; Castillo, D.; De´rien, S.; Toupet, L.; Dixneuf, P. H.
Angew. Chem., Int. Ed. 2003, 42, 5474.
(9) Osipov, S. N.; Golubev, A. S.; Sewald, N.; Michel, T.; Kolomiets,
A. F.; Fokin, A. V.; Burger, K. J. Org. Chem. 1996, 61, 7521.
(10) General procedure: in a Schlenk tube under inert atmosphere, to a
solution of the enyne (1 mmol) in degassed diethyl ether (2 mL) was added
1.15-1.2 mmol of the 2.0 M trimethylsilyldiazomethane solution in ether.
The mixture was stirred at room temperature, and 5 mol % of the precatalyst
Cp*RuCl(COD) was then introduced. Pure ethyldiazoacetate was similarly
added to a dioxane solution, and the reaction was performed at 100 °C.
Reaction completion was monitored using GC or TLC techniques. Dias-
tereoisomers were separated as pure compounds using standard chroma-
tography over silica gel with an ether:pentane eluting mixture. All bicyclic
compounds were fully characterized.
The proposed mechanism for this transformation
(Scheme 1, R ) SiMe3) involves the formation of ruthena-
(11) See Supporting Information.
3742
Org. Lett., Vol. 7, No. 17, 2005

yet, it appears that the ruthenacyclobutane C, when [Ru] is
the Cp*(Cl)Ru moiety, favors reductive elimination with
respect to the (IMes)Cl2Ru moiety leading to metathesis.3
However, in the reaction of an enyne containing an internal
triple bond with catalyst RuCl2(dCHPh)(PCy3)(IMes), a
small amount of bicyclo[3.1.0]hexane was obtained.12
Scheme 1. Proposed Mechanism
This sequential carbene addition and cyclopropanation
reactions of the fluorinated enynes 2 and 3 offer a direct
route to bicyclic R-amino esters containing the alkenyl
bicyclo[3.1.0] and [4.1.0]alkane structure. Previously, only
a bicyclic fluorinated lactam was obtained via addition of
N2C(CF3)(CO2Me), with Rh2(OAc)4 catalyst, to benzyl-
protected allylamine followed by deprotection via hydroge-
nation.13
The reaction described here constitutes the first observed
direct route to bicyclic amino acid derivatives from easily
made enynes and to new fluorinated bicyclic compounds. It
surprisingly shows that the Cp*(Cl)Ru moiety in the presence
of N2CHR inhibits the RCM of enynes. This simple
ruthenium-catalyzed reaction seems to offer potential for the
access to a wide variety of amino acid derivatives and
functional bicyclic compounds and to become as general as
the transformation of enynes into alkenyl cycloalkenes with
alkene metathesis catalysts. The adaptation of this reaction
to natural amino acid derivatives is under study.
cyclobutene A, as for the initial step of RCM of enynes with
alkene metathesis catalysts.3 Indeed, an initial bicyclization
cannot be attained as in the Pt(II)-catalyzed transformation
of enynes,4 as the enyne is unchanged in the presence of
Cp*(Cl)Ru(COD) and in the absence of diazoalkane com-
pound. Simple models show that the formation of intermedi-
ate A requires the anti position of Cp* and SiMe3 groups to
decrease steric interactions (Scheme 1). The transformation
of A into the alkenylcarbene B is responsible for the initial
configuration of the alkenyl group. The opening of the Ru-C
bond leading to intermediate B requires a “disrotary” process
to explain the initial Z-configuration of the -CHdCHSiMe3
chain. An interaction between the neighboring Me3Si and
Cl groups may be responsible for this stereochemistry. The
[2 + 2] addition of the carbene and terminal double bond in
B is expected to give the metallacyclobutane intermediate
C, which on reductive elimination leads to the transformation
of the bicyclic products 4 and 5.
Acknowledgment. This work was supported by the
CNRS, via the PICS 2105 CNRS-Russian Academy of
Science, the Russian Foundation of Basic Research (Grant
N030322000) and the Ministe`re de la Recherche. The authors
are grateful to the latter for a Ph.D. grant to M.E., and to
the European Union for support via the COST Program D17.
Supporting Information Available: Spectroscopic data
for compounds 4 and 5 and 7 and 8 (PDF), and structural
data for minor diastereoisomer 5c (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
It is noteworthy that the same sequential steps A f B f
C occur in the transformation of enynes with an alkene
metathesis catalyst, such as RuCl2(dCHPh)(PCy3)(IMes).3
Although theoretical calculations have not been performed
OL051393F
(12) Kitamura, T.; Sato, Y.; Mori, M. AdV. Synth. Catal. 2002, 344, 678.
(13) Paulini, K.; Reissig, H.-U. J. Prakt. Chem. 1995, 337, 55.
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