Ruthenium-catalyzed cyclotrimerization of 1,6- and 1,7-azadiynes: New access to fluorinated bicyclic amino acids

Article abstract of DOI:10.1055/s-2008-1032089

An efficient access to a variety of trifluoromethyl-substituted cyclic α-amino acid derivatives based on ruthenium-catalyzed cyclotrimerization of appropriate 1,6- and 1,7-diynes with terminal and internal alkynes has been developed. Georg Thieme Verlag S

Full text of DOI:10.1055/s-2008-1032089

578
LETTER
Ruthenium-Catalyzed Cyclotrimerization of 1,6- and 1,7-Azadiynes:
New Access to Fluorinated Bicyclic Amino Acids
F
luorinated Bicyc
l
r
ic
A
min
i
o Acidsgorii T. Shchetnikov,a Sergey N. Osipov,*a Christian Bruneau,b Pierre H. Dixneuf*b
a
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov str. 28, 119991 Moscow, Russian
Federation
Fax +7(495)1355085; E-mail: osipov@ineos.ac.ru
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France
E-mail: pierre.dixneuf@univ-rennes1.fr
b
Received 29 November 2007
make this reaction the key step in a series of elegant syn-
theses of biologically relevant structures including natural
products. To the best of our knowledge, this catalytic
alkyne cyclotrimerization approach to produce cyclic
amino acids has been applied only in rare examples. Thus,
Kotha, starting from appropriate 1,7-diacetylenic precur-
sors has applied Vollhardt’s [CoCp(CO)2] and Wilkin-
son’s [RhCl(PPh3)3] catalysts for the synthesis of some
TIC derivatives as constrained analogues of phenylala-
nine. However, the yields of the corresponding cyclic
products were poor to moderate even upon increased
amounts of catalyst (more then 10 mol%).13
Yamamoto and Itoh14 have introduced RuCl(Cp*)(cod) as
a catalyst for [2+2+2]-cycloaddition of diynes to different
types of unsaturated compounds such as functionalized
olefins, alkynes, nitriles, isocyanates and isothiocyanates
to provide an efficient access to a variety of aromatic and
heteroaromatic compounds. Generally, this catalyst pre-
cursor has proved to be effective in amounts from 1 mol%
to 3 mol% to afford good yields of the desired cycload-
ducts. This efficiency is likely due to the ability of the
RuCl(C5R5) moiety to generate, after oxidative coupling
of a diyne, a biscarbene intermediate rather than a classi-
cal ruthenacyclopentadiene.15 Being inspired by these re-
sults we have investigated the catalytic activity of
RuCl(Cp*)(cod) in cyclotrimerization of fluorinated
diynes.
Abstract: An efficient access to a variety of trifluoromethyl-substi-
tuted cyclic a-amino acid derivatives based on ruthenium-catalyzed
cyclotrimerization of appropriate 1,6- and 1,7-diynes with terminal
and internal alkynes has been developed.
Key words: fluorinated diynes, amino acids, ruthenium catalysis,
cyclotrimerization, alkynes
Peptides modified by nonproteinogenic amino acids (AA)
are useful building blocks for drug discovery. Therefore,
the development of new synthetic pathways to non-natu-
ral amino acids containing various functionalities remains
a constant challenge. On the other hand, a-amino acids
containing the trifluoromethyl (CF3) group1 are of partic-
ular interest due to the unique characteristics of the tri-
fluoromethyl group, such as high electronegativity,
electron density, steric hindrance and hydrophobicity.2
The advantages of peptides modified by CF3-AA include
enhanced proteolytic stability, affinity for lipid bilayer
membranes, as well as stabilization of secondary su-
pramolecular structures3 owing to the ability of the fluo-
rine atom to form hydrogen bonds.4,5
Previously we described the syntheses of a-CF3-AA de-
rivatives (e.g. such as CF3-ornithine,6a CF3-arginine,6b
CF3-thalidomide6c) based on addition of C-nucleophiles to
acylimines of 3,3,3-trifluoropyruvates.7 Unsaturated a-
CF3-AA derivatives obtained by this methodology were
successfully further applied in ruthenium-mediated met-
athesis-type reactions to afford new families of the corre-
sponding proline and pipecolic acid derivatives.8 Now we
disclose a new effective access to a-trifluoromethyl-sub-
stituted derivatives of tetrahydroisoquinoline-3-carboxyl-
ic acid (TIC) and benzoproline via ruthenium-catalyzed
co-cyclotrimerization of a-CF3-a-amino esters bearing
two terminal alkyne chains with terminal and internal
alkynes.
We have first developed an effective protocol for the
preparation of new trifluoromethyl-containing 1,6- and
1,7-azadiynes starting from readily available imines of
methyltrifluoropyruvate. The synthetic sequence includes
two simple stages: (i) the addition of sodium acetylenide16
or allenylmagnesium bromide17 to electrophilic imines 1
takes place under mild conditions to give the correspond-
ing a-alkynyl derivatives 2 and 3 (Scheme 1); (ii) the N-
alkylation of alkynyl-substituted amino esters with prop-
argyl bromide, after deprotonation with sodium hydride in
DMF, affords azadiynes 4 and 5 with acceptable yields
(Table 1).
Inter- and intramolecular cyclotrimerization of acetylenes
catalyzed by a variety of transition metal catalysts9 has
been recognized as a versatile synthetic approach for
highly substituted benzene derivatives.10 Cobalt-11 and
rhodium-based12 catalysts have been successfully used to
We found that cyclotrimerization of both 1,6- and 1,7-aza-
diynes with terminal alkynes proceeded at room tempera-
ture in DCE in the presence of 1 mol% of RuCl(Cp*)(cod)
and led to completion of reaction after few minutes in the
case of 1-hexyne and after one to two hours for acetylene
(gas, normal pressure) to give CF3-containing proline18
and TIC derivatives18 in high yields (Table 2, entries 1, 2,
SYNLETT 2008, No. 4, pp 0578–0582
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1032089; Art ID: G36707ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Fluorinated Bicyclic Amino Acids
Electron-deficient alkynes
biscarboethoxyacetylene) did not form cyclotrimerization
products even under more drastic conditions.
579
troscopy.
(e.g.
F3C
CH CNa, THF
1.
Cbz
OMe
N
H
2. H+, H2O
Blechert and his co-workers19 have shown that triynes can
undergo an intramolecular cascade of metathesis reac-
tions to provide the corresponding arene derivatives using
Grubbs’ catalyst B. Later, Roy20 and Witulski21 have suc-
cessfully demonstrated its application in an intermolecu-
lar version of alkyne co-cyclotrimerization. Based on
these findings we have checked the catalytic activity of B
in cyclotrimerization of fluorinated substrates. Thus, we
found that B was also able to perform cyclotrimerization
1,6- and 1,7-azadiynes 4 and 5 in amount of 5 mol% at
room temperature in DCE, although the yields of reaction
products appeared slightly lower than those with A
(Table 2, entries 5, 7, 8).
O
2 (67 %)
F3C
CO2Me
N
PG
1
1. H2C=C=CH–MgBr
2. H+, H2O
F3C
PG
OMe
N
H
O
3
PG = Boc (3a, 54%), Cbz (3b, 69%), SO2Ph (3b, 55%)
Scheme 1 Synthesis of a-CF3-a-amino acid derivatives with alkyne
substituents in the a-position
Table 1 Synthesis of Fluorinated 1,6- and 1,7-Azadiynes
F3C
F3C
Whereas the action of the Grubbs catalyst is explained by
successive alkyne/metal–carbene metathesis steps,19 the
most efficient co-cyclotrimerization by precatalyst A can
be rationalized as described in Scheme 2. The first step
corresponds to the oxidative coupling of the diyne to give
the ruthenacyclopentadiene I close to the transition state
affording the more stable biscarbene intermediate II.15 A
Ru–carbene bond of II can add regioselectively to alkyne
bond, via a metathesis step, affording the new biscarbene
ruthenium intermediate III, leading to the reductive elim-
ination step via IV that is closed to the transition state. The
identical reactivity of both Ru=C bonds of II is expected
to give the two observed regioisomers (1:1).
1. NaH, DMF, 0 °C
n
n
PG
OMe
MeO2C
N
H
N
, r.t.
Br
2.
PG
O
4, 5
2, 3
Entry
PG
n
0
1
1
1
Product
Yield (%)
1
2
3
4
Cbz
Boc
Cbz
SO2Ph
4
50
55
75
71
5a
5b
5c
To obtain free cyclic amino acids the methods for selec-
tive removal of protection groups from amino and carbox-
ylic functions have been applied via standard protocols
commonly used in peptide chemistry. Thus, Cbz-protec-
tive group could be easily removed by catalytic (10% Pd/
C) hydrogenation in methanol at room temperature; sub-
sequent basic hydrolysis of ester with KOH led to forma-
tion of the desired free amino acid22 (Scheme 3).
5–8). With 1-hexyne, the two regioisomers were formed
in 1:1 ratio.
Internal alkynes such as diphenylacetylene and diethyl-
acetylene reacted with diynes under the same conditions
leading to the formation of the corresponding cycload-
ducts 6c, 6d and 7e in poor to good yields (Table 2, entries
3, 4, 9). In these cases, dimers of starting diynes were de-
tected as by-products according to NMR and MS spec-
F3C
F3C
MeO2C
PG
R
N
MeO2C
[Ru]
N
PG
H
I
R
F3C
MeO2C
[Ru]
Ru
N
PG
Cl
II
A
F3C
R
R
F3C
MeO2C
PG
R
F3C
MeO2C
MeO2C
PG
H
N
N
[Ru]
N
[Ru]
PG
III
H
IV
Scheme 2 Proposed mechanism for cyclotrimerization catalyzed by RuCl(Cp*)(cod)
Synlett 2008, No. 4, 578–582 © Thieme Stuttgart · New York

580
G. T. Shchetnikov et al.
LETTER
Table 2 a-CF3-Substituted Benzoproline and Tetrahydroisoquinoline Derivatives
R1
R2
CF3
F3C
CO2Me
R1
R2
PCy3
Ru
Cl
n
n
[Ru]
CO2Me
[Ru] =
+
Ru
N
DCE, r.t.
N
Ph
Cl
PG
Cl
PG
PCy3
4, 5
6, n = 0
7, n = 1
A
B
Entry
Diyne
Acetylene
Product
[Ru] catalyst A/B
Time (min)
Yield (%)
82
CF3
CF3
MeO2C
CO2Me
1
HC≡CH
A
120
Cbz
N
N
Cbz
CF3
N
6a
CF3
CF3
CF3
CF3
CF3
CF3
MeO2C
CO2Me
CO2Me
2
3
4
5
6
7
BuC≡CH
PhC≡CPh
EtC≡CEt
HC≡CH
A
10
76
Bu
Cbz
N
Cbz
6b
CF3
N
Ph
MeO2C
A
120
240
120
10
20
Cbz
N
Ph
Cbz
6c
CF3
MeO2C
CO2Me
A
40
N
Cbz
N
Cbz
6d
7a
CF3
CO2Me
MeO2C
A/B
A
86/71
70
N
Cbz
N
Cbz
CF3
CO2Me
MeO2C
Bu
BuC≡CH
BuC≡CH
N
N
N
Cbz
N
Cbz
7b
CF3
CO2Me
MeO2C
Bu
A/B
10
89/72
Boc
N
Boc
7c
CF3
CF3
CO2Me
MeO2C
Bu
8
9
BuC≡CH
PhC≡CPh
A/B
10
82/67
25
PhO2S
N
SO2Ph
7d
CF3
CF3
Ph
MeO2C
CO2Me
A
120
N
Cbz
N
Cbz
Ph
7e
In conclusion, we have developed an effective approach compounds obtained can be useful candidates for specific
to CF3-substituted benzoproline and tetrahydroisoquino- modification of biologically active peptides.
line-3-carboxylic acid derivatives based on ruthenium-
catalyzed cyclotrimerization of 1,6- and 1,7-azadiynes
with RuCl(Cp*)(cod) and the Grubbs catalyst. The new
Acknowledgment
This work was supported by the Russian Foundation of Basic Rese-
arch (grants NN 07-03-00593 and 07-03-92171-CNRS).
Synlett 2008, No. 4, 578–582 © Thieme Stuttgart · New York

LETTER
Fluorinated Bicyclic Amino Acids
581
(12) Neeson, S. J.; Stevenson, P. J. Tetrahedron Lett. 1988, 29,
813.
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CF3
CF3
n
H2, Pd/C
MeOH
n
CO2Me
CO2Me
N
N
H
CBz
8 (n = 0, 73%)
9 (n = 1, 85%)
6a (n = 0)
7a (n = 1)
(14) (a) Yamamoto, Y.; Hata, K.; Arakawa, T.; Itoh, K. Chem.
Commun. 2003, 1290. (b) Yamamoto, Y.; Okuda, S.; Itoh,
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(h) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.;
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CF3
CO2Me
5% KOH in MeOH
1 h, 20 °C
N
H
10 (99%)
Scheme 3 The synthesis of free amino acids
References and Notes
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Raleigh, D. P. J. Am. Chem. Soc. 2003, 125, 9286.
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Chemistry: Principles and Commercial Applications;
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(18) General Procedure for Ru-Catalyzed
Cyclotrimerization: The catalyst RuCl(Cp*)(cod) (2
mol%) was added to the solution of diyne (0.15 mmol) and
alkyne (0.6 mmol) in degassed DCE under an argon
atmosphere. The resulting mixture was stirred at r.t. until the
reaction completion (TLC control). The solvent was
removed under reduced pressure and the crude product was
purified by column chromatography on silica gel (eluent:
EtOAc–PE).
Data for Compound 6a: oil. 1H NMR (400 MHz, DMSO-
d6, 80 ºC): d = 3.61 (br s, 3 H, OMe), 4.84 (d, JAB = 15.2 Hz,
1 H, NCH2), 5.03 (d, JAB = 15.2 Hz, 1 H, NCH2), 5.23 (s, 2
H, OCH2), 7.34–7.56 (m, 9 H, Ar). 19F NMR (282 MHz,
DMSO-d6, TFA, 80 °C): d = 5.3 (s, 3 F, CF3). Anal. Calcd
for C19H16F3NO4: C, 60.16; H, 4.25; N, 3.69. Found: C,
60.21; H, 4.35; N, 3.67.
Data for Compound 7a: oil. 1H NMR (400 MHz, DMSO-
d6, 80 °C): d = 3.33 (d, JAB = 15.4 Hz, 1 H, CH2), 3.39 (d,
JAB = 15.4 Hz, 1 H, CH2), 3.50 (s, 3 H, OMe), 4.49 (d, JAB
=
15.1 Hz, 1 H, NCH2), 4.87 (d, JAB = 15.1 Hz, 1 H, NCH2),
5.15 (s, 2 H, OCH2), 7.29 (m, 4 H, Ar), 7.33–7.43 (m, 5 H,
Ph). 19F NMR (282 MHz, CDCl3, TFA, 80 °C): d = 6.32 (s,
3 F, CF3). 13C NMR (150.9 MHz, DMSO-d6, 80 ºC): d =
32.51, 45.15, 56.21, 68.18, 70.10 (q, 2JC–F = 28.4 Hz), 122.23
(q, 1JC–F = 288.2 Hz), 127.88, 127.91, 128.04, 134.70,
136.51, 139.18, 156.32, 165.81. Anal. Calcd for
C20H18F3NO4: C, 61.07; H, 4.61; N, 3.56. Found: C, 60.99;
H, 4.55; N, 3.67.
(9) Bird, C. W. Transition Metal Intermediates in Organic
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(10) For a review on synthetic applications of transition-metal-
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Chem. Res. 1977, 10, 1.
(19) Peters, J.-U.; Blechert, S. Chem. Commun. 1997, 1983.
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Chem. Commun. 2000, 1965.
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53; Angew. Chem. 1984, 96, 525.
Synlett 2008, No. 4, 578–582 © Thieme Stuttgart · New York

582
G. T. Shchetnikov et al.
LETTER
(22) Data for Compound 10: mp 234 °C (dec.). 1H NMR (300
MHz, DMSO-d6): d = 3.35 (d, JAB = 15.4 Hz, 1 H, CH2), 3.39
(d, JAB = 15.4 Hz, 1 H, CH2), 3.86 (d, JAB = 15.5 Hz, 1 H,
NCH2), 4.06 (d, JAB = 15.5 Hz, 1 H, NCH2), 7.23 (m, 4 H,
Ar). 19F NMR (282 MHz, DMSO-d6): d = 3.07 (s, 3 F, CF3).
13C NMR (150.9 MHz, DMSO-d6): d = 31.03, 45.12, 64.01
(q, 2JC–F = 29.9 Hz), 120.91 (q, 1JC–F = 281.3 Hz), 127.31,
128.01, 128.41, 129.21, 133.81, 138.14, 168.41. Anal. Calcd
for C12H12F3NO2: C, 53.88; H, 4.11; N, 5.71. Found: C,
53.61; H, 4.32; N, 5.34.
Synlett 2008, No. 4, 578–582 © Thieme Stuttgart · New York

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