Ruthenium-catalysed synthesis of fluorinated bicyclic amino esters through tandem carbene addition/cyclopropanation of enynes

Article abstract of DOI:10.1002/chem.201101209

The reaction of fluorinated 1,6- and 1,7-enynes, containing the moiety N(PG)C(CF₃)(CO₂R), with diazo compounds in the presence of [RuCl(cod)(Cp*)] (cod=cycloocta-1,5-diene, Cp=C₅Me ₅, PG=protecting group) as the catalyst precursor leads to the formation of fluorinated 3-azabicyclo[3.1.0]hexane-2-carboxylates and 4-azabicyclo-[4.1.0]heptane-3-carboxylates. This catalytic transformation was applied to various protecting groups and has proved to be a selective and a general synthetic tool to form constrained proline or homoproline derivatives in good yields. Z stereoselectivity of the created alkenyl group is obtained with N₂CHSiMe₃, whereas N₂CHCO₂Et favours selectively the E configuration for the same double bond. The diastereoselectivity exo/endo depends on the size of the created ring. The X-ray structures of two products have been determined, showing the stereochemistry of the compounds. The reaction can be understood by initial [2+2] addition of the Ru=CHY bond, generated from diazoalkane, with the C≡CH bond of the enyne leading to a key bicyclic ruthenacyclobutane, which promotes the cyclopropanation, rather than metathesis. This selective formation of bicyclic [n.1.0] compounds results from the ruthenium-catalysed creation of three carbon-carbon bonds in a single step under mild conditions. Copyright

Full text of DOI:10.1002/chem.201101209

DOI: 10.1002/chem.201101209
Ruthenium-Catalysed Synthesis of Fluorinated Bicyclic Amino Esters
through Tandem Carbene Addition/Cyclopropanation of Enynes
Matthieu Eckert,[a] Solenne Moulin,[a] Florian Monnier,[a] Igor D. Titanyuk,[b]
Sergey N. Osipov,[b] Thierry Roisnel,[c] Sylvie Dꢀrien,*[a] and Pierre H. Dixneuf[a]
Abstract: The reaction of fluorinated
1,6- and 1,7-enynes, containing the
constrained proline or homoproline de-
rivatives in good yields. Z stereoselec-
tivity of the created alkenyl group is
obtained with N2CHSiMe3, whereas
N2CHCO2Et favours selectively the E
configuration for the same double
bond. The diastereoselectivity exo/endo
depends on the size of the created ring.
The X-ray structures of two products
have been determined, showing the ste-
reochemistry of the compounds. The
reaction can be understood by initial
[2+2] addition of the Ru=CHY bond,
generated from diazoalkane, with the
moiety N(PG)C
diazo compounds in the presence of
[RuCl(cod)(Cp*)] (cod=cycloocta-1,5-
ACHTUNGTRENNUNG(CF3)HCATUNGTRENN(UGN CO2R), with
A
ACHTUNGTRENNUNG
ꢀ
diene, Cp*=C5Me5, PG=protecting
group) as the catalyst precursor leads
to the formation of fluorinated 3-
C CH bond of the enyne leading to a
key bicyclic ruthenacyclobutane, which
promotes the cyclopropanation, rather
than metathesis. This selective forma-
tion of bicyclic [n.1.0] compounds re-
sults from the ruthenium-catalysed cre-
ation of three carbon–carbon bonds in
a single step under mild conditions.
azabicycloACHTUNGTRENNUNG[3.1.0]hexane-2-carboxylates
and 4-azabicyclo-[4.1.0]heptane-3-car-
boxylates. This catalytic transformation
was applied to various protecting
groups and has proved to be a selective
and a general synthetic tool to form
Keywords:
amino
acids
·
bicyclic products · diazoalkanes ·
enynes · ruthenium
Introduction
Among them, fluorinated amino acids can be considered as
interesting building blocks for designing hyperstable protein
folds or to obtain highly specific protein–protein interac-
tions.[4] Moreover, 19F NMR spectroscopy is an effective tool
for conformational studies of fluorine-containing peptides.
As they can considerably improve the profile of bioactive
peptides, the synthesis of fluorinated a-amino acids has re-
cently received increasing attention.[5]
The incorporation of cyclic a-amino acids into key posi-
tions of peptide chains constitutes the most prominent path-
way leading to conformationally constrained peptidomimet-
ics.[6] Although biological activities have been shown by the
incorporation of the fluorinated group into bicyclic amino
acids,[7] only few fluorinated strained bicyclic amino acid de-
rivatives have been described due to the lack of a straight-
forward method of access.[5c]
It occurs that a possible approach could involve catalytic
carbocyclisation of enynes. Indeed, transition-metal-catalyst-
promoted enyne cycloisomerisation is one of the most gen-
eral and efficient methods for the synthesis of functionalised
cyclic and heterocyclic compounds,[8] including bicyclic prod-
ucts.[9–12] Among them, the preparation of bicyclic [n.1.0] de-
rivatives is of importance since the cyclopropane ring is a
frequent moiety in natural products.[8f] This type of transfor-
mation was first reported from allylpropargylethers into 3-
Peptides modified by nonproteinogenic amino acids are
useful building blocks for drug discovery. In particular, a,a-
disubstituted amino acids have been the subject of growing
interest because their incorporation into peptides can lead
to specific biological activities,[1] as they are able to stabilize
secondary structure elements and to retard proteolytic deg-
radation.[2] Due to the unique properties of the fluorine
atom, such as high electronegativity and hydrophobicity, flu-
orinated compounds have become very important in the
field of medicinal chemistry and in pharmaceuticals.[3]
[a] Dr. M. Eckert, Dr. S. Moulin, Dr. F. Monnier, Dr. S. Dꢀrien,
Prof. P. H. Dixneuf
Laboratoire Catalyse et Organomꢀtalliques
UMR 6226-Sciences Chimiques de Rennes
CNRS-Universitꢀ de Rennes 1, Campus de Beaulieu
35042 Rennes (France)
Fax : (+33)223236939
E-mail: sylvie.derien@univ-rennes1.fr
[b] Dr. I. D. Titanyuk, Dr. S. N. Osipov
A.N. Nesmeyanov Institute of Organoelement Compounds
Russian Academy of Sciences (INEOS)
Vavilov, st.28, Moscow 119991 (Russia)
[c] Dr. T. Roisnel
Centre de diffractomꢀtrie X
oxabicyclo
ACHTUNGTRNEUN[NG 4.1.0]heptenes in the presence of PtCl4 catalys-
UMR 6226-Sciences Chimiques de Rennes
CNRS-Universitꢀ de Rennes 1, Campus de Beaulieu
35042 Rennes (France)
t.[10a] Later, various bicyclo
ACTHNUGTENR[NUG 4.1.0]heptenes have been ob-
tained by bicyclisation of 1,6-enynes with Pt,[10a–f] Au,[10g–i]
Ir[10j] and Rh[10k] catalysts. This cycloisomerisation applied to
1,5-enynes possessing no heteroatom on their tethers led to
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101209.
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FULL PAPER
bicyclo[3.1.0]hexenes
or
hexanes.[11]
Few
bicyclo-
ACHTUNGTRENNUNG[3.1.0]hexane derivatives have been prepared from 1,6-
enynes in the presence of Ru,[12a] Au,[12b] Pt,[12c] Pd[12d–e] or
Bi[12f] catalysts. However, none of these examples was ap-
plied to amino acid derivative synthesis.
Our studies concerning the catalytic activity of the com-
Scheme 3. Synthesis of fluorinated alkenylamino esters.
plex
[RuCl
G
T
(cod=cycloocta-1,5-diene)
showed its ability to produce ruthenium–carbene species, in
situ generated from diazo compounds, and their catalytic ad-
dition to alkynes.[14] This work led to the discovery of a cata-
lytic cascade rearrangement of enynes into bicyclic deriva-
tives (Scheme 1).[15]
Table 1. Synthesis of fluorinated enynes. Boc=tert-butoxycarbonyl;
Cbz=carbobenzyloxy.
PG
n
Enyne
Yield [%]
Scheme 1. Synthesis of bicyclic compounds by the catalytic rearrange-
ment of enynes. Cp*= C5Me5 .
Boc
Cbz
Ts
Boc
Cbz
Ts
0
0
0
1
1
1
1a
1b
1c
2a
2b
2c
71
72
53
51
55
60
The mild conditions of this ruthenium-catalysed reaction,
assuming that it might tolerate classical protecting groups of
amino acid functionalities, prompted us to explore the
access to novel bicyclic constrained fluorinated amino
esters.[16]
The 1,6-enynes 1 were reacted with 1.15 equivalents of tri-
We now report the first synthesis of fluorinated 3-
methylsilyldiazomethane in diethyl ether in the presence of
azabicyclo
G
5 mol% of the precatalyst [RuClACHTGUNTRENNU(G C5Me5)ACHTNUGTREN(NGNU cod)] (I) affording
[4.1.0]heptane-3-carboxylates, according to the same meth-
odology, by ruthenium-catalysed tandem carbene addition/
cyclopropanation of fluorinated enynes containing the
À
a complete conversion of 1 in 4 h at room temperature. Flu-
orinated bicyclic proline derivatives were obtained
(Table 2). These aminoester derivatives 3/3’ containing the
moiety N(PG) CACHTUNGTRENNUNG(CF3)ACHTUGNTREN(NUGN CO2R), leading to the first fluorinat-
ed bicyclic proline and pipecolic acid derivatives
(Scheme 2). Indeed, despite the interest of substituted pro-
lines, there are few reports of syntheses of fluorinated pro-
line and pipecolic acid derivatives.[17]
Table 2. Reaction of 1,6-enynes with trimethylsilyldiazomethane.
PG
Yield[a] (3+3’) [%]
Ratio 3/3’
Boc (a)
Cbz (b)
Ts (c)
80
60
59
57:43
62:38
68:32
Scheme 2. Synthesis of fluorinated bicyclic proline and pipecolic acid de-
rivatives.
[a] Yield of isolated product.
Results and Discussion
strained bicyclicACTHNGUTERNNU[G 3.1.0]hexane structure were isolated in
good yields (59–80%) up to 80% for the Boc protecting
group. In each case, the selective Z configuration of the cre-
ated double bond was observed. Two diastereoisomers, 3
and 3’, were formed. NOESY NMR spectroscopic experi-
ments showed the relative cis configuration of the vinyl and
CF3 groups for each major isomer, 3a–c. An approximately
60:40 ratio for 3/3’ was obtained for the Boc and Cbz pro-
tecting groups and it increased until approximately 70:30
for the tosyl group. These reaction conditions have been
chosen because they were proved to be the best for the
same reaction with simple nitrogenated enynes.[15] For this
The preparation of the fluorinated enynes 1–2 has been first
achieved from the protected imines CF3CACTHNUTRGNEUNG
(=NPG)CO2Me[18]
by nucleophilic addition of vinyl or allyl magnesium bro-
mide to produce fluorinated alkenylamino esters
(Scheme 3).[19]
The second step involved the deprotonation of the amino
ester derivatives with NaH in DMF at 08C and subsequent
alkylation with propargylbromide to afford the correspond-
ing 1,6- and 1,7-enynes with various protecting groups
(Table 1).
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S. Dꢀrien et al.
reaction, the bulky electron-rich precursor [RuCl
(cod)] (I) appeared to be a selective catalyst, whereas
[RuCl2A(C6Me6)]2 or [Ru(C5Me5)(CH3CN)3]PF6 did not cata-
lyse it. The use of the precatalyst [RuCl(C5H5)(cod)] led to
(C5Me5)-
G
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
E
G
N
G
N
a lower conversion of enynes even after 24 h and a mixture
of isomers was obtained.
Table 3. Reaction of 1,6-enynes with ethyldiazoacetate.
Crystals of the minor isomer 3’c that were suitable for X-
ray analysis were obtained and the crystallographic structure
displayed a relative trans configuration for the vinyl and CF3
groups and a Z configuration for the alkenyl moiety
(Figure 1).[20]
PG
Yield[a] (5+5’) [%]
Ratio 5/5’
Boc (a)
Cbz (b)
Ts (c)
70
65
77
57:43
56:44
69:31
[a] Yield of isolated product.
A complete selectivity towards the E configuration of the
double bond for each compound was observed. Two diaste-
reoisomers, 5 and 5’ were isolated by silica gel chromatogra-
phy and the cis/trans relationship between the vinyl and CF3
groups for each major isomer were assigned by NOESY
NMR spectroscopic experiments, which indicated that the
major diastereoisomer was the same as for the proline deriv-
atives 3/3’. For the Boc and Cbz protecting groups, the ratio
5/5’ was only approximately 55:45 but a higher ratio of
69:31 was obtained with the tosyl group.
Figure 1. ORTEP drawing of the molecular structure of 3’c.
To demonstrate the possible further synthetic application
of bicyclic amino acid derivatives, for example, in peptide
synthesis, the deprotection of amino function in the corre-
sponding Boc derivatives was performed. Proline derivative
5a was treated with TFA at room temperature to lead to
the desired free amino ester 6a in 92% yield (Scheme 5).
The desilylation of trimethylsilylvinylbicycloACHTUNTRGNEU[GN 3.1.0]hexanes
appeared not to take place under classical conditions. How-
ever the direct formation of bicyclic compounds with a desi-
lylated vinyl group have already been obtained from simple
nitrogenated enynes by reaction with N2CHSiMe3 in metha-
nol, in presence of catalyst I. Indeed, the in situ formation
of diazomethane from N2CHSiMe3 could be obtained in
methanol.[15b] The reaction of 1,6-enyne 1b with 1.1 equiva-
lents of trimethylsilyldiazomethane in methanol at room
temperature led after 15 min to desilylated fluorinated pro-
line derivatives 4b/4’b in 61% yield (Scheme 4). The ratio
of the two diasteroisomers was similar to the ratio 3b/3’b.
The same catalytic rearrangement could be carried out by
using another diazoalkane as the substituent source for the
formed alkenyl moiety. 1,6-Enynes 1a–c were reacted with
1.2 equivalents of ethyldiazoacetate and 5 mol% of [RuCl-
Scheme 5. Deprotection of Boc-derivative 5a. TFA=trifluoroacetic acid.
Fluorinated bicyclic pipecolic acid derivatives were thus
expected to be produced by extension of the catalytic trans-
formation to 1,7-enynes 2a–c. By reaction with trimethylsi-
lyldiazomethane in diethyl ether at room temperature, the
corresponding 4-azabicyclo-[4.1.0]heptane-3-carboxylates 7/
7’ were produced in 64–73% yields (Table 4). As for the re-
action of the 1,6-enynes with N2CHSiMe3, a Z configuration
for the double bond was obtained for each compound 7/7’.
Two diastereoisomers 7 and 7’ were isolated but contrary
to the reaction of the 1,6-enynes, NOESY NMR spectro-
scopic experiments showed that the diastereoisomer 7’ with
the relative trans configuration of the vinyl and CF3 groups
Scheme 4. Reaction of 1,6-enyne 1b with trimethylsilyldiazomethane in
methanol.
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Ruthenium-Catalysed Synthesis of Fluorinated Bicyclic Amino Esters
Table 4. Reaction of 1,7-enynes with trimethylsilyldiazomethane.
FULL PAPER
ester derivatives 9/9’ in reasonable yields (48–57%)
(Table 5). An E stereochemistry was obtained for the
double bond as for the reaction of the 1,6-enynes under sim-
Table 5. Reaction of 1,7-enynes with ethyldiazoacetate.
PG
Yield[a] (7+7’) [%]
Ratio 7’/7
Boc (a)
Cbz (b)
Ts (c)
68
64
73
53:47
55:45
67:33
[a] Yield of isolated product.
PG
Yield[a] (9+9’) [%]
Ratio 9’/9
Boc (a)
Cbz (b)
Ts (c)
48
49
57
60:40
58:42
68:32
was now the major isomer in each case. These data could be
further confirmed by a crystallographic structure of the
major isomer 7’c (Figure 2).[20]
[a] Yield of isolated product.
ilar conditions. Diastereoisomer 9’ with the relative trans
configuration of the vinyl and CF3 groups, established by
NOESY NMR spectroscopic experiments for each com-
pound, was the major isomer formed as for the reaction of
the 1,7-enynes with N2CHSiMe3 giving pipecolic acid deriva-
tives 7/7’.
The N-deprotection of pipecolic acid derivatives has been
carried out from a silylated compound. The reaction of Boc-
derivative 7’a with HCl 12n in AcOEt at 08C led to simul-
taneous desilylation and N-deprotection affording free
amino ester 10’a (Scheme 7).
Figure 2. ORTEP drawing of the molecular structure of 7’c.
Scheme 7. Deprotection of Boc-derivative 7’a.
When the reaction of N-Boc-protected 1,7-enyne 2a with
N2CHSiMe3 was performed in methanol, desilylated bicyclic
pipecolic acid derivatives 8a/8’a were obtained in 70% yield
To study the effect of the CF3 substituent on the obtained
diastereoselectivity, the synthesis of monosubstituted 1,7-
enyne 11, with only a CF3 group, was performed. This 1,7-
enyne 11 was obtained from a-(trifluoromethyl)homoallyla-
mine,[21] which was first protected by a tosyl group and then
alkylated with propargylbromide (Scheme 8).
with
a ratio of 50:50 for the two diastereoisomers
(Scheme 6).
With ethyldiazoacetate, 1,7-enynes 2a–c afforded in diox-
ane at 1008C after 4–5 h the corresponding bicyclic amino-
Scheme 8. Synthesis of 1,7-enyne 11.
The reaction of trifluoromethylated 1,7-enyne 11 with
N2CHSiMe3 in the presence of 5 mol% of catalyst I at room
temperature in diethyl ether led to the corresponding bicy-
Scheme 6. Reaction of 1,7-enyne 2a with trimethylsilyldiazomethane in
methanol.
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S. Dꢀrien et al.
clic compounds 12/12’ as a mixture of isomers in a low yield
(38%; Scheme 9). However, it was possible to determine
that the double bond was formed in a Z/E mixture with a
ratio of 80:20. Two diastereoisomers, 12’ and 12 were ob-
served by 1H NMR spectroscopy in a ratio of 60:40.
Scheme 9. Reaction of 1,7-enyne 11 with trimethylsilyldiazomethane.
1
Based on the comparison of the H NMR spectroscopic
chemical shifts of the other fluorinated pipecolic acid deriv-
atives, we arrived at the conclusion that the major diastereo-
isomer had the CF3 and vinyl groups in a trans relationship
as in the derivatives 7’. This hypothesis was confirmed by
the following experiment.
When the reaction of 1,7-enyne 11 was carried out with
N2CHCO2Et at 1008C, a good yield of compounds 13/13’
(80%) was obtained with the complete E stereochemistry
for the double bond (Scheme 10). The two diastereoisomers
Scheme 11. Proposed catalytic cycle.
nal triple bond of the enyne.[14] A classical [2+2] cycloaddi-
ꢀ
tion of Ru=C and C C bonds gives the metallacyclobutene
A, leading to the ruthenium vinylcarbene B. The intramolec-
ular interaction of the Ru=C bond with the terminal C=C
bond of B is expected to give the metallacyclobutane inter-
mediate C, which is subject to reductive elimination to give
a fluorinated bicyclic aminoester.
Scheme 10. Reaction of 1,7-enyne 11 with ethyldiazoacetate.
The catalytic enyne metathesis has been shown to easily
proceed with Grubbs catalyst[22] and the proposed mecha-
nism involves the interaction of the Ru=C bond with the
triple bond by means of a mechanism similar to that in
were formed with a ratio 13’/13 of 60:40. NOESY NMR
spectroscopic experiments confirmed the relative trans con-
figuration for the CF3 and vinyl groups for the major isomer
13’ as for derivatives 9’. The comparison with derivatives 9/
9’c possessing two substituents (CF3 and CO2Me groups)
showed that a loss of diastereoselectivity was observed.
Scheme 11, with [RuCl2ACTHUNGTRENNN(UG =CHPh)AHCNUTRTGENG(NUN IMes)CATHGUNTREN(NUNG PCy3)], except for
the last step. In this latter case, the intermediate C exclu-
sively leads to a metathesis process. Thus, the present reac-
tion differs from enyne metathesis only by the ability of the
{Cp*RuCl} moiety to favour reductive elimination. DFT cal-
culations have been performed with simple enynes[15b] and
have confirmed that the {(C5R5)RuCl} fragment favours the
formation of a cyclopropanation product and inhibits the
enyne metathesis.
Proposed mechanism
Catalytic cycle: A possible mechanism for this formation of
fluorinated 3-azabicyclo
ACHTUNGTRENNUNG
azabicyclo-[4.1.0]heptane-3-carboxylates
Scheme 11. This catalytic cycle is similar to that proposed
for the cyclisation of simple enynes under similar condi-
tions.[15b]
Stereochemistry: Simple molecular models show that the for-
mation of intermediate A requires the anti position of Cp*
and Y groups to decrease strong steric interactions present
in the syn isomer. Thus, the stereochemistry of the double
bond results from the opening of the metallacyclobutene A
(Scheme 12). With Y=CO2Et, electronic repulsion between
Cl and CO2Et groups favours the opening leading to lower
steric hindrance giving an E configuration (A1). For Y=
SiMe3, a strong interaction between SiMe3 and Cl groups is
It is known that the complex [RuClACTHNUTRGENN(UG C5Me5)ACHTUNGTRENN(UGN cod)] easily
loses its cod ligand in the presence of unsaturated substrates,
thus offering two vacant coordination sites for the activation
of two unsaturated bonds. Diazo compounds are expected
to interact with the precatalyst [RuCl
ACHUTGTNRNE(NUG C5Me5)AHCTUNGTREN(NGUN cod)] to give
ruthenium–carbene species, which first react with the termi-
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Ruthenium-Catalysed Synthesis of Fluorinated Bicyclic Amino Esters
FULL PAPER
ic tool as it can be used as well to form proline derivatives
than to produce homoproline derivatives, in good yields.
High stereoselectivities for the created alkenyl chain can be
obtained, depending on the nature of the diazoalkane: Z
isomer with N2CHSiMe3 and E isomer with N2CHCO2Et.
These results allow us to consider a ruthenium vinyl–car-
bene species as a key intermediate of the reaction, responsi-
ble for the stereoselectivity. Importantly, the last catalytic
step involving the formation of ruthenacyclobutane species
selectively forms a cyclopropane ring by reductive elimina-
tion instead of an alkenylcycloalkene by an alkene metathe-
sis process. This single-step access route to amino acid deriv-
atives represents an alternative synthesis for the formation
of constrained analogues of natural amino acids.
Scheme 12. Stereochemical aspects of intermediates A.
expected and can be responsible for the opposite opening in
spite of steric interactions leading to Z configuration (A2).
However, when Y=SiMe3, it was shown with simple
enynes[15] that the stereoselectivity depends also on the allyl
arm substitution. A substituted double bond on the allyl
arm induced a total Z stereoselectivity, whereas with a ter-
minal double bond a Z/E mixture (Z favoured) was ob-
tained. A possible coordination of this double bond, when it
is not substituted, on the ruthenium centre in intermediate
A, can disturb the Cl—SiMe3 interaction and partially leads
to E stereochemistry (A3). A hindered double bond is not
able to coordinate the ruthenium and thus only the expected
Z stereochemistry is obtained. In the case of aminoester de-
rivatives, the same results are obtained with the substitution
of the alkenyl chain by introduction of two substituents
(CF3 and CO2Me groups) close to the N atom. All the com-
pounds with CF3 and CO2Me groups produce exclusively Z
stereochemistry (A2), whereas the products 12/12’ with CF3
group only are obtained with a Z/E stereochemistry.
For these trifluoromethylated bicyclic proline and pipecol-
ic acid derivatives, the diastereoselectivity exo/endo depends
strongly on the size of the created ring. The fluorinated pro-
line derivatives favour the diastereoisomer with the relative
cis configuration of the vinyl and CF3 groups, whereas the
six-membered ring derivatives favour the diastereoisomer
with the trans configuration. This diastereoselectivity endo/
exo is probably due to electronic (strong electronegativity of
CF3 group) and steric effects. The electronic repulsion be-
tween Cl and CF3 groups is expected to strongly induce the
favoured position of the CF3 group. For proline derivatives,
the X-ray analysis shows a restricted space above the five-
membered ring on the side of cyclopropane ring. This can
explain the anti position of the cyclopropane ring and the
CF3 group for the major diastereoisomer for these com-
pounds.
Experimental Section
General: All catalytic reactions were carried out under inert atmosphere
in Schlenk tubes. The complex [RuClACTHNUTRGENNUG(C5Me5)ACHTUTGNREN(NUGN cod)] was prepared accord-
ing to the reported method.[23] 1H and 13C NMR spectra were recorded
on Bruker 300, 400 and 500 MHz and DPX 200 spectrometers in deuter-
ated chloroform solutions at 298 K. Mass spectra were obtained on
VARIAN MATT 311 high-resolution spectrometer in Centre Regional
de Mesures de l’Ouest (CRMPO) of the University of Rennes1. Charac-
terization data are presented in the Supporting Information.
Typical procedure for enynes synthesis: In a Schlenk tube under an inert
atmosphere, a solution of alkenylamino acid derivative[19] (3 mmol) in dry
DMF (2 mL) was added to a suspension of NaH (3.3 mmol) in dry DMF
(2 mL) at 08C. After stirring for 1 h at room temperature propargyl bro-
mide (6 mmol) was added and reaction mixture was stirred overnight.
Cold water was added and solution was extracted with ether. The organic
layer was washed with brine and dried with MgSO4. The organic solvent
was then removed under reduced pressure and the crude product was pu-
rified by silica gel chromatography.
Typical procedure for catalytic carbene addition/cyclopropanation of
enynes: (Trimethylsilyl)diazomethane solution in diethyl ether (2.0m,
1.15 mmol) or ethyldiazoacetate (1.2 mmol) was added in a Schlenk tube
under inert atmosphere to a solution of the enyne (1 mmol) in degassed
diethyl ether, dioxane or methanol (2 mL). Precatalyst [RuCl
ACHTUNGTRENNUNG(C5Me5)-
AHCTUNGERTG(NNUN cod)] (5 mol%) was then introduced. The mixture was stirred at room
temperature or at 1008C for 4–5 h. Reaction completion was monitored
by using GC or TLC techniques. The solvent was removed under vacuum
and diastereoisomers were separated as pure compounds by using stan-
dard chromatography over silica gel with a diethyl ether/pentane eluting
mixture.
Acknowledgements
This work was supported by the CNRS, the Russian Academy of Scien-
ces, and the Russian Foundation of Basic Research, via the PICS-4249
and GDRI-611 projects, and the European Union through the network
IDECAT. The authors are grateful for support, to the Ministꢂre de la Re-
cherche for a PhD grant to M.E. and F.M. and to the Region Bretagne,
through an ARED program for a PhD grant to S.M.
Conclusion
We have successfully developed a straightforward synthetic
route for the synthesis of novel highly constrained a-trifluor-
omethyl a-amino acid derivatives. This catalytic reaction
leads to the first trifluoromethylated bicyclic proline and pi-
pecolic acid derivatives, under mild conditions, in one step
from easily accessible enynes. This [RuClACTHUNTRGENN(UG C5Me5)ACHTUNGTRNE(NUGN cod)]-cat-
alysed transformation can be applied to various protecting
groups and has proved to be a selective and general synthet-
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Published online: July 5, 2011
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