Diastereoselective synthesis of fluorinated, seven-membered β-amino acid derivatives via ring-closing metathesis

Article abstract of DOI:10.1021/ol034827k

(Matrix presented) Cis and trans seven-membered γ,γ -difluorinated β-amino acid derivatives (III) have been prepared with a sequence that starts with imidoyl halides (I), which are condensed with suitable ester enolates to give intermediates (II). These,

Full text of DOI:10.1021/ol034827k

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2523-2526
Diastereoselective Synthesis of
Fluorinated, Seven-Membered â-Amino
Acid Derivatives via Ring-Closing
Metathesis
Santos Fustero,* Ana Bartolome´, Juan F. Sanz-Cervera, Mar´ıa Sa´nchez-Rosello´,
Juan Garc´ıa Soler, Carmen Ram´ırez de Arellano,† and Antonio Simo´n Fuentes
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia,
E-46100 Burjassot, Spain
santos.fustero@uV.es
Received May 14, 2003
ABSTRACT
Cis and trans seven-membered γ,γ-difluorinated â-amino acid derivatives (III) have been prepared with a sequence that starts with imidoyl
halides (I), which are condensed with suitable ester enolates to give intermediates (II). These, in turn, can be cyclized by means of a ring-
closing olefin metathesis reaction and the product stereoselectively reduced to yield compounds (III) in good overall yields.
â-Amino acids are an important class of organic molecules
that appear in Nature either free or as part of peptides or
depsipeptides.1 They are present in the structures of natural
peptides displaying antibiotic, antifungal, and citotoxic
properties, among others.1 Dolastatin,2 jasplakinolide,3 and
taxol4 are notable examples of natural products that not only
include â-amino acid units in their structure but also display
extremely interesting biological activities. In contrast to their
nonfluorinated derivatives, very little is known about the
chemistry and biological activity of fluorine-containing
â-amino acids.5 Furthermore, the replacement of hydrogen
atoms by fluorine atoms has been found to sometimes
provide dramatic changes in the physical and biological
properties of organic compounds.6
Another interesting aspect of â-amino acid chemistry is
the ability of these compounds to form â-peptides. These
biopolymers require fewer monomers than R-peptides to
adopt a variety of stable secondary structures.7 Cyclic
â-amino acids are also extremely useful intermediates in the
synthesis of natural products, â-peptides, and peptidomi-
metics.8 The introduction of a ring into the structure of the
(5) (a) Fluorine-containing Amino Acids: Synthesis and Properties;
Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley: Chichester, UK, 1994.
For recent papers, see: (b) Fustero, S.; Pina, B.; Salavert, E.; Navarro, A.;
Ram´ırez de Arellano, M. C.; Simo´n, A. J. Org. Chem. 2002, 67, 4667-
4679 and literature therein. (c) Soloshonok, V. A.; Ohkura, H.; Sorochinsky,
A.; Voloshin, N.; Markovsky, A.; Belik, M.; Yamazaki, T. Tetrahedron
Lett. 2002, 43, 5445-5448 and literature therein.
† To whom correspondence regarding X-ray analysis should be directed.
(1) (a) EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E., Ed.;
Wiley-VCH: New York, 1997. (b) Liu. M.; Sibi, M. P. Tetrahedron 2002,
58, 7991-8035.
(6) (a) Banks, R. E.; Tatlow, J. C.; Smart, B. E. Organofluorine
Chemistry: Principles and Commercial Applications; Plenum Press: New
York, 1994. (b) Houben-Weyl Methods of Organic Chemistry, Workbench
Edition: Georg Thieme Verlag: Stuttgart, 2000; Vols. E10a-c.
(7) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001,
101, 3219-3232.
(2) Pettit, G. R.; Kamano, Y.; Kizu, H.; Dufresne, C.; Herald, C. L.;
Bontems, R.; Schdmidt, J. M.; Boettner, F. E.; Nieman, R. A. Heterocycles
1989, 28, 553-558.
(3) Grieco, P. A.; Hon, Y. S.; Pe´rez-Medrano, A. J. Am. Chem. Soc.
1988, 110, 1630-1631.
(4) Ojima, I.; Lin, S.; Wang, T. Curr. Med. Chem. 1999, 6, 927-954.
(8) Fu¨lo¨p, F. Chem. ReV. 2001, 101, 2181-2204.
10.1021/ol034827k CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/17/2003

â-amino acid confers more rigidity to the structure of the
peptides and, in many cases, an improved stability and
biological activity.9 An interesting example of a natural,
cyclic â-amino acid that appears as a free molecule is
cispentacin, a compound that displays potent antifungal
activity, in particular against Candida albicans.10
Scheme 1
Although the literature includes some examples of the
synthesis of cyclic â-amino acids, those with seven-
membered rings are particularly scarce.8 In fact, to the best
of our knowledge, no fluorinated, seven-membered â-amino
acids have been described thus far.
The ring-closing olefin metathesis reaction (RCM) has
been one of the most successful methods for the preparation
of medium- or large-sized rings from acyclic diene precur-
sors.11 Two of the most widely used ruthenium catalysts for
this reaction appear in Figure 1.12
described by Appel et al.15 and later improved by Uneyama
et al.16 In this way, the protected imidoyl chlorides 5a-c
were successfully prepared as shown in Scheme 2.
Scheme 2
The ethyl and benzyl esters of 4-pentenoic acid (6a, R )
Et; 6b, R ) Bn) were then treated with 2 equiv of LDA5b in
THF at -78 °C to generate their enolates, which were then
treated with 1 equiv of the imidoyl chlorides 5 to yield the
fluorinated â-imino esters 4 (Table 1). In general, the yields
Figure 1. First- (1) and second-generation (2) Grubbs’ catalysts.
Despite its versatility, however, the RCM has been used
infrequently for the preparation of fluorinated nitrogen
compounds.13 Indeed, the literature contains only two
examples in which nonfluorinated, six-membered â-amino
acids are prepared by means of this reaction.14
Table 1. Results for the Reaction between the Esters 6 and the
Imidoyl Chlorides 5
In this letter, we describe the first diastereoselective
synthesis of the cis- and trans-2-amino-3,3-difluorocyclohept-
5-ene carboxylic acid derivatives 3. The retrosynthetic
analysis for the strategy we followed is shown in Scheme 1.
In this approach, the key step is a ring-closing metathesis
reaction that gives compounds 3. The fluorinated imidoyl
chlorides 5 were prepared with the methodology first
entry
3
5
Ar
R
product
yield (%)a
(9) See, for example: Appella, D. H.; Christianson, L. A.; Klein, D. A.;
Richards, M. R.; Powell, D. R.; Gellman, S. M. J. Am. Chem. Soc. 1999,
121, 7574-7581.
1
2
3
4
6a
6a
6a
6b
5a
5b
5c
5a
p-MeOC6H4
o-MeOC6H4
p-FC6H4
Et
Et
Et
Bn
4a
4b
4c
4d
85
80
82
76
(10) Kawabata, K.; Inamoto, Y.; Sakane, K.; Iwamoto, T.; Hashimoto,
S. J. Antibiotics 1990, 43, 513-518.
p-MeOC6H4
(11) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
(b) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036-
2056. (c) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-388.
(d) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446-
452. (e) Roy, R. Chem. Commun. 2000, 519-529. (f) Percy, J. M.; Pintat,
S. Chem. Commun. 2000, 607-608. (g) Kariuki, B. M.; Owton, W. M.;
Percy, J. M.; Pintat, S.; Smith, C. A.; Spencer, N. S.; Thomas, A. C.; Watson,
M. Chem. Commun. 2002, 228-229.
a Yields for purified products.
for the condensation reaction between the esters 6 and the
imidoyl chlorides 5 were good (Table 1). The H and 19F
1
NMR spectra showed that, while in two cases the imino
tautomer was the only product present (entries 1 and 2), in
the other two cases a mixture of the imino and enamino forms
was present (entries 3 and 4), with the former being more
abundant.
(12) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041. (b) Scholl, M.; Ding, S.; Lee,
C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956. (c) Jafarpour, L.; Hillier,
A. C.; Nolan, S. P. Organometallics 2002, 21, 442-444.
(13) (a) Osipov, S. N.; Artyushin, O. I.; Kolomiets, A. F.; Bruneau, C.;
Picquet, M.; Dixneuf, P. H. Eur. J. Org. Chem. 2001, 3891-3897. (b)
Fustero, S.; Navarro, A.; Pina, B.; Garc´ıa Soler, J.; Bartolome´, A.; Asensio,
A.; Simo´n, A.; Bravo, P.; Fronza, G.; Volonterio, A.; Zanda, M. Org. Lett.
2001, 3, 2621-2624.
(15) Appel, R.; Warning, K.; Ziehn, K. D. Chem. Ber. 1973, 106, 2093-
2097.
(16) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.; Uneyama,
K. J. Org. Chem. 1993, 58, 32-36.
(14) (a) Abell, A. D.; Gardiner, J. Org. Lett. 2002, 4, 3663-3666. (b)
Perlmutter, P.; Rose, M.; Vounatsos, F. Eur. J. Org. Chem. 2003, 756-
760.
2524
Org. Lett., Vol. 5, No. 14, 2003

A priori, two different approaches were possible for the
next step: either first reducing the CdN bond and then
attempting an RCM reaction or performing the RCM reaction
first and then reducing the imine. Both reaction sequences
were explored. Compound 4a was first reduced with
NaCNBH3 in THF/TFA17 at 0 °C with 70% yield, albeit
with no stereoselectivity, as both possible syn and anti
diastereoisomers were formed in 1:1 ratio (syn-7a and anti-
7a, Scheme 3). Attempts to increase the diastereoselectivity
Scheme 3a
Figure 2. Ellipsoid plot of compound cis-8a (50% probability
level).
that the substituents on C-1 and C-2 were in a cis relative
configuration (Figure 2).19
Since this strategy of performing the RCM after the
reduction produced poor results, the obvious alternative
consisted of inverting the order of the reactions, that is,
having the RCM reaction precede the CdN bond reduction.
In principle, this alternative strategy might have the advan-
tage of a reduced basicity of the imino group, as compared
to that of the amino group, and hence a better compatibility
with the catalyst. The first attempts to carry out the RCM
reaction with Grubb’s first-generation catalyst12a (PCy3)2Cl2-
RudCHPh (1) on compound 4a yielded the desired product
9a in 65% yield. These moderate yields prompted new
attempts with the second-generation catalyst (IHMes)-
(PCy3)Cl2RudCHPh12b (2), which had a shorter reaction time
(6 h) and produced higher yields (75%). The remaining
compounds 4 were treated in a similar fashion to yield the
cyclized compounds 9. The results are shown in Table 2.
a Conditions: (a) NaCNBH3 (3 equiv)/THF/TFA/0 °C. (b)
Aqueous saturated NH4Cl solution.
through the use of different reducing agents and conditions
(e.g., NaBH4/ZnI2/CH2Cl2)5b were not fruitful.
Syn- and anti-7a were separated by means of column
chromatography and independently treated with the com-
mercially available ruthenium alkylidene catalyst (IHMes)-
(PCy3)Cl2RudCHPh12b (2) in refluxing CH2Cl2 to check the
validity of this approach. The yields for the resulting cyclized
compounds cis- and trans-8a, however, were disappointingly
low (Scheme 4).18
Scheme 4
Table 2. Results for the RCM Reaction of Compounds 4
reaction
temp
R1 catalyst (°C)
time
(h)
yield
product (%)a
entry
Ar
1
2
3
4
5
6
p-MeOC6H4 Et
p-MeOC6H4 Et
p-MeOC6H4 Et
o-MeOC6H4 Et
1
1
2
2
2
2
25
40
40
40
40
40
36
24
6
6
6
9a
9a
9a
9b
9c
9d
65
60
75
90
60
65
The relative configuration of the ester and amino groups
in compounds 8 was determined by means of X-ray diffrac-
tion techniques. A single crystal of compound 8a was
prepared, and subsequent X-ray diffraction analysis showed
p-FC6H4
Et
p-MeOC6H4 Bn
6
a Yields for purified products.
(17) (a) Bartoli, G.; Cimarelli, C.; Marcantoni, E.; Palmieri, M.; Petrini,
G. J. Org. Chem. 1994, 59, 5328-5335. (b) Cimarelli, C.; Palmieri, G. J.
Org. Chem. 1996, 61, 5557-5563.
(18) The low yields in this reaction could be due to the fact that the free
amine can chelate the ruthenium atom in the catalyst, thus decreasing its
activity. See: (a) Sandford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 6543-6554. (b) Wright, D. L.; Schulte, J. P., II; Page, M.
A. Org. Lett. 2000, 2, 1847-1850.
These results not only indicate that the RCM is an
excellent method for preparing seven-membered rings in
(19) See Supporting Information for X-ray diffraction data of cis-8a.
Org. Lett., Vol. 5, No. 14, 2003
2525

Scheme 5a
Table 3. Results for the Reduction of the â-Imino Esters 9
a Reagents and conditions: (a) Ce(NH4)2(NO3)6/CH3CN-H2O,
0 °C, 2 h, 95% yield. (b) H2 (1 atm), Pd/C (10%), MeOH, 2 h,
99% yield.
starting
entry
material
Ar
R1
product
yield (%)a
1
2
3
4
9a
9b
9c
9d
p-MeOC6H4
o-MeOC6H4
p-FC6H4
Et
Et
Et
Bn
cis-8a
cis-8b
cis-8c
cis-8d
90
88
80
72
cis-8a was removed with ceric ammonium nitrate in aqueous
acetonitrile, followed by treatment with aqueous NaHCO3
and aqueous Na2SO3 sequentially to yield compound cis-
10a in 95% yield (Scheme 5).
p-MeOC6H4
a Yields for purified products.
Finally, the double bond in compound cis-8a was easily
reduced by means of catalytic hydrogenation with Pd/C 10%
as a catalyst in MeOH, yielding compound cis-11a in
quantitative yield after 2 h (Scheme 5).
In summary, the methodology presented here allows for
the diastereoselective synthesis of the seven-membered, γ,γ-
difluorinated â-amino acid derivatives 8, 10, and 11 in an
effective manner. To the best of our knowledge, this is the
first synthesis available for these interesting substances.
Extension of this methodology to the enantioselective
preparation of this and other cyclic, fluorinated â-amino acid
derivatives is in progress.
these kinds of substrates but also that catalyst 2 provides
superior results. The NMR data for the products 9 showed
that they consisted of a mixture of imino/enamino tautomers,
with the first being predominant.
In the next step, the imine was reduced with NaCNBH3
in THF at 0 °C in the presence of TFA (Table 3). This
afforded the protected amino esters in yields of 72-90%
with reaction times of 1-3 h. In all cases, only the cis
diastereoisomer was obtained in a completely diastereose-
lective fashion. The physical and spectroscopic data for
compound cis-8a prepared in this way were the same as those
obtained for the same compound prepared from syn-7a via
the alternative route (see above).
These results bolstered the conclusion that the RCM
followed by reduction is more effective for the preparation
of the cyclic fluorinated â-amino acids 8 than the opposite
sequence, as the products are obtained both in higher yields
and with complete diastereoselectivity. One possible reason
for this may be the added rigidity that the cycle and the imine
group impart on the structures of compounds 9.
Acknowledgment. We thank the Ministerio de Ciencia
y Tecnolog´ıa of Spain for financial support (PPQ2000-0824).
A.B., J.G.S., and M.S.-R. thank the Generalitat Valenciana
and the Ministerio de Educacio´n y Cultura of Spain for
predoctoral fellowships.
Supporting Information Available: Spectroscopic data,
experimental details for compounds 3-5, 7-9, 10a, and 11a,
and crystal data for compound cis-8a in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
To probe the feasibility of the deprotection of these
compounds, the p-MeOC6H4 (PMP) protecting group20 of
(20) Jacob, P.; Callery, P. S.; Shulgin, A. T.; Castagnoli, N. J. Org. Chem.
1976, 41, 3627-3629.
OL034827K
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Org. Lett., Vol. 5, No. 14, 2003