Fluorine-containing α-alkynyl amino esters and access to a new family of 3,4-dehydroproline analogues

Article abstract of DOI:10.1039/b007396m

New α-alkynyl, α-CF₃ amino esters have been prepared from electrophilic imines and used to produce 3-alkenyl-3,4-dehydroproline derivatives, via enyne metathesis with the precatalyst [Ru=C=C=CPh₂(Cl)(PCy₃)(arene)]O₃

Full text of DOI:10.1039/b007396m

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Fluorine-containing a-alkynyl amino esters and access to a new
family of 3,4-dehydroproline analogues¤
David Semeril,a Jerome Le Notre,a Christian Bruneau,a Pierre H. Dixneuf,*a
Alexey F. Kolomietsb and Sergey N. Osipov*b
L e t t e r
a L aboratoire dÏOrganometalliques et Catalyse: Chimie et Electrochimie Moleculaires (CNRS
UMR 6509), Universite de Rennes, Campus de Beaulieu, 35042 Rennes, France.
E-mail: pierre.dixneuf=univ-rennes1.fr
b A N Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
V avilov str. 28, 117813 Moscow, V -334, GSP-1, Russia. E-mail: osipov=ineos.ac.ru
Received (in Montpellier, France) 6th September 2000, Accepted 11th October 2000
First published as an Advance Article on the web 8th December 2000
New a-alkynyl, a-CF amino esters have been prepared from
[Ru2C2C2CR (Cl)(PCy )(p-cymene)]`CF SO ~ [eqn. (1)].
3
2
3
3
3
electrophilic imines and used to produce 3-alkenyl-3,4-
dehydroproline derivatives, ¿ia enyne metathesis with the preca-
talyst [Ru2C2C2CPh (Cl)(PCy )(arene)]O SCF . These new
conjugated Ñuorine-containing dienes are active substrates for
the Diels–Alder reaction and lead to a new class of bicyclic
amino esters.
(1)
2
3
3
3
Electrophilic a-CF , a-CO Me imines constitute excellent
3
2
starting materials for the formation of bifunctional a-CF
a,a-Disubstituted a-amino acids constitute an important class
of nonproteinogenic amino acids that has recently received a
great deal of attention.1 In particular, the incorporation of
these compounds into peptides results in conformational
restrictions and increased rigidity, leading to enhanced resist-
ance towards protease enzymes and to the stabilisation of
some secondary structures.2 Moreover, such a-amino acids
3
a-amino esters.9 The starting electrophilic imines 2a and 2b
were prepared in quantitative yields (90È95%) from the Ñuori-
nated keto ester CF COCO Me, 1,10 upon addition of
3
2
H NTs, H NSO Ph or H NCbz, followed by dehydration11
2
2
2
2
(Scheme 1). The addition of lithium acetylide to an imine 2,
followed by hydrolysis,12 led to the new a-CF , a-alkynyl
3
amino esters 3. The treatment of the amino esters 3 with NaH,
bearing an alkynyl or CF group at the a-position irreversibly
3
followed by allyl bromide addition in DMF, a†orded a-CF
inhibit the action of various pyridoxal phosphate-dependant
3
amino esters 4 with the 1,6-enyne structure (Scheme 1). Thus,
enzymes3 such as alanine racemases4a or decarboxylases.4b On
the other hand, increasing interest in new proline derivatives is
connected with the fact that proline is unique among the
natural amino acids for its abilities to induce b-turns and initi-
ate peptide folding of the a-helix.5 Due to these structurally
important properties, proline is often regarded as the primary
contributor to the biological activity of several proteins, as
well as having a key role in biological recognition processes.5
Structurally modiÐed prolines, especially those containing
multiple CÈC bonds, have been described as potential enzyme
inhibitors.6 For example, 3,4-dehydro-L-proline is an e†ective
inhibitor of proline dehydrogenase.7
the derivatives 4a (R \ H), 4b (R \ Bun), 4c (R \ CH OMe),
2
4d (R \ cyclopropyl) and 4e [R \ C(Me)2CH ] were obtained
2
in overall yields of 40, 42, 60, 50 and 28%, respectively,
directly from the imines 2a–c without puriÐcation of the inter-
mediates 3. Similarly, the a-CF Cl-containing imine
2
CF Cl(CO Me)C2N-Boc, 2d,13 led to the new a-alkynyl-N-
2
2
allyl amino ester 5 [eqn. (2)].
Simple syntheses of new a,a-disubstituted amino acids, con-
taining a-alkynyl and a-CF groups, are of interest as proline
3
derivative precursors. As ruthenium-allenylidene complexes of
(2)
the type (LnRu2C2C2CR )`PF ~ were recently shown to be
excellent catalyst precursors for enyne metathesis in the syn-
thesis of dihydrofuran derivatives,8 it might be expected that
a-alkynyl, a-CF a-amino esters could o†er a direct access to
2
6
The catalytic enyne metathesis on the Ñuorinated enynes 4
was then attempted. A solution of the a-CF amino ester 4a
3
3
(0.2 mmol) in toluene (5 mL) with 10 mol.% of catalyst
unsaturated cyclic amino esters, and especially to unsaturated
[Ru2C2C2CPh (Cl)(PCy )(p-cymene)]`PF ~, A,14,15 was
proline analogs.
2
3
6
irradiated at 300 nm for 0.5 h at room temperature and then
the mixture was heated at 80 ¡C for 69 h in order to reach
90% conversion of 4a. The 5-membered cyclic amino ester 6
resulting from enyne metathesis was isolated in 70% yield
(Scheme 2). Thus, the catalyst A appears to be less active
towards the bulky enynes 4 than in the enyne metathesis of
smaller mixed propargyl allyl ethers to give dihydrofurans.8
The reaction of 4a was then performed with 5 mol.% of the
We now report (i) general access to a variety of a-CF a-
alkynyl amino esters from the readily available electrophilic
imines (CF )(CO Me)C2NR and (ii) their use for access to 5-
membered ring, Ñuorinated amino esters via enyne metathesis
3
3
2
performed with the ruthenium-allenylidene precatalyst
¤ Dedicated to the memory of Professor Olivier Kahn
16
New J. Chem., 2001, 25, 16È18
DOI: 10.1039/b007396m
This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2001

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Scheme 1 Reagents and conditions: (i) H N-PG [H NTs or H NSO Ph (without solvent) or H NBoc or H NCbz (both in dichloromethane)];
2
2
2
2
2
2
(ii) SOCl in excess ([5 equiv.) with a catalytic amount of pyridine for PG \ Ts or SO Ph; (iii) 1 equiv. of triÑuoroacetic anhydride (TFAA), 2
2
2
equiv. of pyridine for PG \ Cbz or Boc; (iv) 1 equiv. of RC3 CLi in THF and then hydrolysis; (v) 2 equiv. of NaH and then allyl bromide (3
equiv.) in DMF.
at 80 ¡C) to yield the cyclic amino ester 9 (56%) (Scheme 2).
The amino esters 6–9 contrast well with the cyclic amino
esters obtained via alkene metathesis18 as they contain a diene
moiety and are potentially suitable precursors for DielsÈAlder
reactions. Thus, the diene 6 was reÑuxed with 3 equiv. of
EtO CC3 CCO Et in toluene for 18 h and the DielsÈAlder
2
2
adduct 10 was isolated in 77% yield, showing the presence of
two diastereoisomers in a 7 : 1 ratio. Compound 10 was aro-
matized on treatment with dichlorodicyanobenzoquinone
(DDQ; 5 equiv.). After 24 h of reÑux in toluene only 50% of
10 was converted, however, the new Ñuorine-containing
bicyclic amino ester 11 was isolated in 37% yield (Scheme 3).
The above reactions show that the ruthenium-allenylidene
complex B is a useful catalyst for access to bicyclic amino
esters.
Scheme 2
salt catalyst, but with
a
di†erent counter anion,
[Ru2C2C2CPh (Cl)(PCy )(p-cymene)]`CF SO ~,
B.15,16
2
3
3
3
After irradiation for 0.5 h at room temperature, only 24 h of
heating in toluene at 80 ¡C led to 95% conversion of 4a and to
the isolation of 6 in 58% yield. Thus, the triÑate catalyst B
appeared to tolerate the CF group as well, brought the best
3
compromise for this enyne metathesis and was selected for
further use.
Catalyst B is easily prepared in situ, just before use for the
transformation of 0.2 mmol of enyne, from 14 mg (2 ] 10~2
mmol) of the very stable salt [RuCl(PCy )(p-cymene)]`TfO~,
3
C,16 and 4 mg of HC3 CÈCPh OH (1 equiv.) in 2 mL of
2
toluene. After 30 min of stirring at room temperature, the
enyne (0.2 mmol) was then introduced and the enyne metath-
esis performed as described above. The stable salt C simply
results from the quantitative one-pot transformation of the
commercial precursor [RuCl (p-cymene)] on addition of 1
Scheme 3
2
2
equiv. of PCy , to produce RuCl (PCy )(p-cymene),16 fol-
3
2
3
lowed by the reaction with 1 equiv. of AgOTf. The metathesis
of enynes 4b and 4c, containing a disubstituted C3 C bond,
required more forcing conditions. Enyne 4b (0.2 mmol) with
10 mol.% of catalyst B in toluene, after 0.5 h UV irradiation
followed by 4 days at 80 ¡C, led to 86% conversion and 40%
of isolated derivative 7. Analogously, after 3 days at 80 ¡C, 4c
led to 48% conversion into 8 isolated in 14% yield (Scheme 2).
In contrast, the novel cyclopropyl (4d) and isopropenyl (4e)
derivatives were not transformed under these conditions. This
is likely due to the bulkiness of the cyclopropyl and isopro-
penyl groups, since the C3 C bond is expected to initially inter-
Experimental
General procedure for the preparation of 3
The imine 2 (5 mmol) in dry THF (15 ml) was added dropwise
to a stirred solution of 6 mmol of lithium acetylide at [78 ¡C.
After 1 h at [78 ¡C the reaction mixture was allowed to
warm up to room temperature and stirred for 5 h. The reac-
tion was quenched with a saturated solution of NH Cl and
extracted with diethyl ether (2 ] 20 ml). The organic layer was
washed with brine (25 ml), dried over MgSO and Ðltered.
4
4
act with the catalyst.17 The N-Boc-protected a-CF Cl enyne 5
The solvent was removed under reduced pressure and the
crude product, characterized by 1H NMR, was used directly
2
containing the a-HC3 C group is transformed under similar
conditions as for 4a (5 mol.% of B, 0.5 h irradiation, and 25 h
without puriÐcation.
New J. Chem., 2001, 25, 16È18
17

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General procedure for the preparation of 4 and 5
(CH N), 53.43 (OCH ), 61.78 (CH CH ), 62.71 (CH CH ),
2
3
3
2
3
2
72.79 (q, 2J \ 29.7, CCF ), 122.21 (CH CH2C), 128.43 (q,
CF
3
2
A solution of 3 (3 mmol) in dry DMF (9 ml) was added to a
suspension of NaH (6 mmol) in dry DMF (15 ml) at 0 ¡C. The
mixture was stirred at room temperature for 0.5 h and then 9
mmol of allyl bromide (in solution in 6 ml of DMF) were
added. After stirring for an additional 5 h, the mixture was
hydrolyzed with water (20 ml) and extracted with diethyl ether
(2 ] 20 ml). The organic layer was washed with water (4 ] 20
1J \ 285.5 Hz, CF ), 127.26, 129.15, 133.33 (aromatic CH),
CF
3
133.83
[CH C(CO)2C],
[CHC(CO)2C], 165.70 (quat. CH2C), 164.87, 166.39, 167.21
(C2O).
135.60
(ipso
C),
139.85
2
11. 1H NMR (CDCl , 200.132 MHz): d 1.33 (t, 3 H,
3
3J \ 7.1, CH CH ), 1.34 (t, 3 H, 3J \ 7.1, CH CH ), 3.83 (s, 3
3
2
3
2
ml), dried over MgSO and Ðltered. The solvent was removed
H, OCH ), 4.34 (q, 2 H, 3J \ 7.1, CH CH ), 4.35 (q, 2 H,
4
3
3
2
under reduced pressure and the crude product was puriÐed by
3J \ 7.1, CH CH ), 4.69 (d, 1 H, 2J \ 14.4, CH N), 5.18 (d, 1
3
2
2
2
Ñash chromatography (diethyl etherÈpentane). Compounds
4a–e and 5 were characterized by 1H, 13C and 19F NMR and
gave satisfactory elemental analyses.
H, 2J \ 14.4, CH N), 7.44È7.61 (m, 4 H, aromatic H), 7.71 (d,
1 H, 3J \ 7.71 Hz, aromatic H), 7.88È7.98 (m, 2 H, aromatic
H). 19F NMR (CDCl , 282.408 MHz): d [72.51 (s, 3 F, CF ).
3
3
13C NMR (CDCl , 50.329 MHz): d 14.04 (CH CH ), 14.12
4a. 1H NMR (CDCl , 200.132 MHz): d 2.75 (s, 1 H,
3
3
2
(CH CH ), 53.78 (OCH ), 54.48 (CH N), 62.20 (CH CH ),
3
C3 CH), 3.97 (s, 3 H, OCH ), 4.00È4.27 (m, 2 H, CH N), 4.87
3
2
3
2
3
2
62.32 (CH CH ), 72.95 (CCF ), 126.02, 127.47, 129.23, 133.32,
3
2
(dm, 1 H, 3J \ 10.1, cis-CH 2CH), 4.94 (dm, 1 H, 3J \ 16.9
Hz, trans-CH 2CH), 5.52È5.74 (m, 1 H, CH 2CH), 7.44È7.65
3
2
3
133.50 (aromatic C), 128.6, 134.77 (quat. aromatic C, CC2O),
132.7 (q, 1J \ 283.0 Hz, CF ), 128.60, 136.60, 138.53, 139.22
(quat. aromatic C), 165.44, 165.72, 166.61 (C2O).
2
2
2
(m, 3 H, Ph), 7.88È7.97 (m, 2 H, Ph). 19F NMR (CDCl ,
CF
3
3
3
188.292 MHz): d [71.9 (s, 3 F, CF ). 13C NMR (CDCl ,
3
50.329 MHz): d 50.60 (NCH ), 54.35 (OCH ), 72.59 (quat. C),
2
3
2
Acknowledgements
The authors wish to thank the European Union INTAS pro-
gramme 97-1874 for support, the COST programme D12/
0025/99 and the Region Bretagne for a grant to J. LN.
80.15 (C3 CH), 97.95 (C3 CH), 117.44 (CH 2CH), 122.39 (q,
1J \ 288.7 Hz, CF ), 128.65, 128.99, 133.60 (aromatic CH),
133.48 (CH 2CH), 139.22 (ipso C), 163.294 (C2O). Anal.
found: C, 49.29; H, 3.68%. Calc. for C
CF
3
2
H
F NO S: C,
15 14 3
4
49.86; H, 3.90%.
References
5. 1H NMR (CDCl , 200.132 MHz): d 1.39 (s, 9 H, 3
3
1
For a review see: H. Heimgartner, Angew. Chem., Int. Ed. Engl.,
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3
3
1991, 30, 238.
4.25 (m, 2 H, CH N), 5.13 (dm, 1 H, 3J \ 10.2, cis-CH 2CH),
2
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2
2
5.25 (dm, 1 H, 3J \ 17.2 Hz, trans-CH 2CH), 5.76È6.04 (m, 1
2
H, CH 2CH). 13C NMR (CDCl , 50.329 MHz): d 28.00 (3
2
3
3
] CH Boc), 50.22 (NCH ), 53.45 (OCH ), 73.93 (quat.
3
4
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2
3
CCF Cl), 79.14 (C3 CH), 82.45 [C(CH ) ], 97.86 (C3 CH),
2
3 3
116.19 (CH 2CH), 128.06 (t, 1J \ 288.6 Hz, CF Cl), 134.25
(CH 2CH), 152.58 (C2O Boc), 163.23 (C2O).
2
CF
2
2
General procedure for the preparation of 6–9
5
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M. Picquet, C. Bruneau and P. H. Dixneuf, Chem. Commun.,
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A mixture of enyne 4 or 5 (1 mmol) and catalyst A or B (5 or
10 mol.%) in toluene was irradiated at room temperature for
0.5 h and then heated at 80 ¡C. The solvent was removed in
vaccum and the crude product was puriÐed by Ñash chroma-
tography (diethyl etherÈpentane). Compounds 6–9 were char-
acterized by 1H, 13C and 19F NMR and gave satisfactory
elemental analyses.
6
7
8
9
6. 1H NMR (CDCl , 200.132 MHz): d 3.87 (s, 3 H, OCH ),
N. Sewald and K. Burger, in Fluorine-containing Amino Acids:
Synthesis and Properties, ed. V. P. Kukhar and V. A. Soloshonok,
Wiley, Chichester, UK, 1995, p. 139, and references cited therein.
3
3
4.03 (d, 1 H, 3J \ 14.8, CH N), 4.53 (d, 1 H, 3J \ 14.8,
2
CH N), 5.21 (d, 1 H, 3J \ 11.4, cis-CH 2CH), 5.47 (d, 1 H,
2
2
3J \ 17.6, trans-CH 2CH), 6.12 (dd, 1 H, 3J \ 11.4, 3J \ 17.7
10 I. L. Knunyants, V. V. Shokina and V. V. Tyuleneva, Dokl. Akad.
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12 The protocol described for analogous compounds in K. Burger
and N. Sewald, Synthesis, 1990, 115 was used.
13 S. N. Osipov, A. S. Golubev, N. Sewald, T. Michel, A. F. Kolo-
miets, A. V. Folkin and K. Burger, J. Org. Chem., 1996, 61, 7521.
14 A. Furstner, M. Picquet, C. Bruneau and P. H. Dixneuf, Chem.
Commun., 1998, 1315.
2
Hz, CH 2CH), 6.19È6.27 (m, 1 H, CH CH2C), 7.43È7.65 (m, 3
2
2
H, Ph), 7.82È7.93 (m, 2 H, Ph). 19F NMR (CDCl , 188.292
3
MHz): d [71.9 (s, 3 F, CF ). 13C NMR (CDCl , 50.329
3
3
3
MHz): d 53.53 (OCH ), 55.02 (CH N), 68.02 (CCF ), 119.16
3
2
(CH 2CH), 123.40 (q, 1J \ 287.4 Hz, CF ), 126.71
CF
(CH CH2), 128.58 (CH 2CH), 127.40, 129.07, 133.22 (aromatic
2
2
3
2
CH), 135.40 (quat. C2), 139.51 (ipso C), 165.65 (C2O). Anal
found: C, 49.71; H, 4.17%. Calc. for C
49.86; H, 3.90%.
H
F NO S: C,
15 14 3
4
Characterization of 10 and 11
15 A. Furstner, M. Liebl, C. W. Lehmann, M. Picquet, R. Kunz, C.
Bruneau, D. Touchard and P. H. Dixneuf, Chem. Eur. J., 2000, 6,
1847.
10 (major diastereoisomer). 1H NMR (CDCl , 200.132
3
MHz): d 1.25 (t, 3 H, 3J \ 7.1, CH CH ), 1.29 (t, 3 H,
3
2
3J \ 7.1 Hz, CH CH ), 3.06È3.20 (m, 1 H, 2CHCH ), 3.50È
16 M. Picquet, D. Touchard, C. Bruneau and P. H. Dixneuf, New J.
3
2
2
Chem., 1999, 23, 141.
3.64 (m, 1 H, 2CHCH ), 3.84 (m, 3 H, CH N and CHCH N),
5.88 (m, 1 H, CH CH2), 7.40È7.62 (m, 3 H, Ph), 7.79È7.91 (m,
2 H, Ph). 19F NMR (CDCl , 282.408 MHz): d [71.62 (s, 3 F,
CF ). 13C NMR (CDCl , 50.329 MHz): d 13.83 (CH CH ),
2
2
2
17 (a) T. J. Katz and T. M. Sivavec, J. Am. Chem. Soc., 1985, 107,
737; (b) T. M. Sivavec, T. J. Katz, M. Y. Chiang and G. X.-Q.
Yang, Organometallics, 1989, 8, 1620.
2
3
18 S. Osipov, C. Bruneau, M. Picquet, A. F. Kolomiets and P. H.
Dixneuf, Chem. Commun., 1998, 2053.
3
3
3
2
14.00 (CH CH ), 29.71 (CH CH2), 38.35 (CHCH N), 52.48
3
2
2
2
18
New J. Chem., 2001, 25, 16È18