First highly diastereoselective synthesis of syn α-methyl β-fluoroalkyl β-amino esters

Article abstract of DOI:10.1021/ol990774o

(matrix presented) A new two-step approach for the diastereoselective synthesis of the syn α-methyl β-fluoroalkyl β-amino esters 4 has been developed. This approach is based on the chemical reduction of the fluorinated β-enamino esters 3, which have been

Full text of DOI:10.1021/ol990774o

ORGANIC
LETTERS
1999
Vol. 1, No. 7
977-980
First Highly Diastereoselective Synthesis
of syn r-Methyl â-Fluoroalkyl â-Amino
Esters
Santos Fustero,* Bele´n Pina, Marta Garc´ıa de la Torre, Antonio Navarro,
Carmen Ram´ırez de Arellano, and Antonio Simo´n
Departamento de Qu´ımica Orga´nica, Facultad de Farmacia, UniVersidad de Valencia,
46100-Burjassot (Valencia), Spain
santos.fustero@uV.es
Received June 30, 1999
ABSTRACT
A new two-step approach for the diastereoselective synthesis of the syn r-methyl â-fluoroalkyl â-amino esters 4 has been developed. This
approach is based on the chemical reduction of the fluorinated â-enamino esters 3, which have been previously obtained from imidoyl chlorides
1 and lithium ester enolates, with ZnI2/NaBH as the reducing agent. The process takes place with high syn diastereoselectivity and good to
4
excellent yields. A metal-chelated six-membered model has been suggested to explain the stereochemical outcome of the reduction reaction.
The study of the chemistry and biological activity of â-amino
acids has aroused considerable interest during the last two
decades.1 The R-methyl derivatives are recognized as an
especially attractive class of â-amino acids; they have been
found (e.g. 2-methyl-3-aminopentanoic acid) to be frame-
work components for several biologically active cyclic
peptides which have been isolated from marine organisms
and which have antifungal, antineoplasic, or cytotoxic
properties.1c,2 These substrates also display enhanced resis-
tance toward protease enzymes when incorporated into
peptidic sequences.1,2 Useful synthetic approaches have
already been reported for the synthesis of R-substituted
â-amino acids;1 most of them have involved alkylation
reactions of the corresponding R-unsubstituted â-amino
acids,1,3 conjugate additions of chiral amines to appropriate
R,â-unsaturated acid derivatives,4 or enzymatic resolution
of racemic R-alkyl â-amino acids.5 However, much less
attention has been given to the stereoselective reduction of
R-alkyl â-enamino acid derivatives, although Palmieri6 and,
more recently, Lhommet7 have described convenient proce-
(3) See for example: (a) Seebach, D.; Estermann, H. Tetrahedron Lett.
1987, 28, 3103. (b) Juaristi, E.; Escalante, J. J. Org. Chem. 1993, 58, 2282
and literature cited therein. (c) Braschi, I.; Cardillo, J.; Tomasini, C.;
Venezia, R. J. Org. Chem. 1994, 59, 7792. (d) Enders, D.; Wahl, H.; Bettray,
W. Angew. Chem., Int. Ed. Engl. 1995, 34, 455. (e) Sewald, N.; Hiller, K.;
Ko¨rner, H.; Findeisen, M. J. Org. Chem. 1998, 63, 7263.
(4) (a) Davies, S. G.; Fenwick, D. R. J. Chem. Soc., Chem. Commun.
1995, 1109. (b) Hawkins, J. M.; Lewis, T. A. J. Org. Chem. 1994, 59, 649.
(c) Enders, D.; Bettray, W.; Raabe, G.; Runsik, J. Synthesis 1994, 1322.
(5) Cardillo, G.; Tolomelli, A.; Tomasini, C. J. Org. Chem. 1996, 61,
8651.
(6) (a) Bartoli, G.; Cimarelli, C.; Marcantoni, E.; Palmieri, G.; Petrini,
M. J. Org. Chem. 1994, 59, 5328. (b) Palmieri, G.; Cimarelli, C. J. Org.
Chem. 1996, 61, 5557.
(7) (a) David, O.; Blot, J.; Bellec, Ch.; Fargeau-Bellasoued, M. C.;
Haviari, G.; Ce´le´rier, J. P.; Lhommet, G.; Gramain, J. C.; Gardette, D. J.
Org. Chem. 1999, 64, 3122. (b) See also: Folmer, J. J.; Acero, C.; Thai,
D. L.; Rapoport, H. J. Org. Chem. 1998, 63, 8170. (c) For asymmetric
hydrogenation of R-unsubstituted â-enamino acid derivatives, see: Lubell,
W. D.; Kitamura, M.; Noyori, R. Tetrahedron: Asymmetry 1991, 2, 543.
(1) Reviews: (a) Cole, D. Tetrahedron 1994, 50, 9517. (b) Juaristi, E.;
Quintana, D.; Escalante, J. Aldrichim. Acta 1994, 27, 3. (c) Cardillo, G.;
Tomasini, C. Chem. Soc. ReV. 1996, 117. (d) EnantioselectiVe Synthesis of
â-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997.
(2) (a) Pettit, G. R.; Kamano, Y.; Kizu, H.; Dufresne, C.; Herald, C. L.;
Bontems, R. J.; Schmidt, J. M.; Boettner, F. E.; Nieman, R. A. Heterocycles
1989, 28, 553. (b) Carter, D. C.; Moore, E. R.; Mynderse, J. S.; Niemczura,
W. P.; Todd, J. S. J. Org. Chem. 1984, 49, 236. (c) Ferna´ndez, R.;
Rodr´ıguez, J.; Quin˜oa, E.; Riguera, R.; Mun˜oz, L.; Ferna´ndez-Suarez, M.;
Debitus, C. J. Am. Chem. Soc. 1996, 118, 11635. (d) Hu, T.; Panek, J. J. J.
Org. Chem. 1999, 64, 3000.
10.1021/ol990774o CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/09/1999

dures for the diastereoselective reduction of cyclic and
acyclic R-substituted â-enamino esters to â-amino esters6,7
or γ-amino alcohols6a with good to moderate diastereo-
selectivity.
strategy is based on a diastereoselective biomimetic trans-
amination of R-alkyl â-keto carboxylic esters to generate the
required fluorinated R-methyl â-amino moiety. The drawback
to this process, as with most of the aforementioned methods
(de 15-36%),13,14 is the low to moderate stereocontrol
observed (de <40%).16
In our method we began by synthesizing the starting
fluorinated â-enamino esters 3 as previously described:11
namely, by treating imidoyl chlorides 117 with lithium
enolates of alkyl propanoates 2-Li in dry tetrahydrofuran
(THF) at -78 °C. This gave rise to the expected R-methyl
â-enamino esters 3, isolated in high yields as a mixture of
enamino and imino tautomers as shown in Table 1.
In addition, the synthesis of fluorinated organic molecules
has received considerable attention recently due to the unique
biological properties imparted by the fluorine atom,8 as well
as their utility in industrial and pharmaceutical applications,
including drug design and mechanistic and metabolic inves-
tigations.9 In connection with ongoing investigations into the
synthesis and reactivity of fluorinated 1,3-difunctionalized
derivatives,10 we report here a new and efficient two-step
approach to fluorinated syn R-methyl â-amino esters 4 by
means of diastereoselective reduction of previously synthe-
sized fluorinated â-enamino esters 3.11 In sharp contrast to
their nonfluorinated derivatives1-7 very little is known about
the synthesis and pharmacological utility of the correspond-
ing â-fluoroalkyl â-amino acids;12 particularly rare are
descriptions of methods for preparing R-substituted â-fluo-
roalkyl â-amino acids. To the best of our knowledge, the
literature includes only four synthetic routes for the dia-
stereoselective synthesis of these substrates. In 1993,13
Kitazume reported the first example of an R-alkyl â-difluo-
romethyl â-amino acid synthesis by means of condensation
of difluoroacetaldimine with enol silyl ethers. More recently,
Be´gue´14 and Uneyama15 have independently described al-
ternative two-step routes to syn and anti (3-fluoroalkyl)-
isoserinates. The Staudinger reaction of ketenes to give
fluorinated aldimines, followed by acidic methanolysis of
the azetidones initially formed,14 and diastereoselective
reduction of R-hydroxy â-imino esters previously obtained
by means of base-catalyzed intramolecular rearrangement of
imino ethers15 are respectively the strategies developed by
the aforementioned authors. Finally, Soloshonok’s group16
has very recently reported an elegant chemoenzymatic
approach to R,â-disubstituted fluorinated â-amino acids. This
Table 1. Fluorinated R-Methyl â-Enamino Esters 3 Obtained
from 1 and 2
entrya
RF
CF3
CF3
CF3
CF2Cl Me
CF3CF2 Me
R2 productb imino/enamino ratioc yield (%)d
1
2
3
4
5
Me
Et
3a
3b
3c
3d
3e
60/40
40/60
30/70
10/90
84/16
92
87
91
72
71
t-Bu
a All reactions were carried out on a 8.0 mmol scale. b R1 ) p-MeOC6H4
(PMP) and R3 ) Me in all cases. c Imino/enamino tautomer ratio estimated
1
by H and 19F NMR on the crude mixture. d Isolated yield.
The conversion of the fluorinated â-enamino esters 3 into
the corresponding â-amino derivatives 4 was accomplished
by means of diastereoselective chemical reduction, as
outlined in Scheme 1 and Table 2. First, we studied the
behavior of 3 toward sodium cyanoborohydride (NaBH3CN)
in a 4:1 mixture of THF and methanolic HCl as the solvent
at room temperature. The process provided high yields of a
syn/anti separable mixture of R-methyl â-fluoroalkyl â-amino
esters 4; however, only moderate diastereoselectivity (de 30-
46%) was observed (entries 1, 11, and 13 in Table 2). Other
reducing agents such as DIBAH, L-Selectride, n-Bu4NBH4,
(8) (a) Banks, R. E.; Tatlow, J. C.; Smart, B. E. Organofluorine
Chemistry: Principles and Commercial Applications; Plenum Press: New
York, 1994. (b) Welch, J. T. SelectiVe Fluorination in Organic and
Bioorganic Chemistry; ACS Symposium Series 456; American Chemical
Society: Washington, DC, 1991. (c) Welch, J. T.; Eswarakrishnan, S.
Fluorine in Bioorganic Chemistry, Wiley: Chichester, U.K., 1991. (d)
German, L.; Zemskov, S. New Fluorinating Agents in Organic Synthesis;
Springer-Verlag: Berlin, Heidelberg, Germany, 1989.
(9) (a) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. Biomedical Aspects
of Fluorine Chemistry; Elsevier: Amsterdam, 1993. (b) Ojima, I.; McCarthy,
J. R.; Welch, J. T. Biomedical Frontiers of Fluorine Chemistry; ACS
Symposium Series 639; American Chemical Society: Washington, DC,
1996. (c) Urban, J. J.; von Tersch, R. L. J. Org. Chem. 1999, 64, 3409 and
literature cited therein.
(10) (a) Fustero, S.; Navarro, A.; D´ıaz, D.; de la Torre, M. G.; Asensio,
A.; Sanz, F.; Liu Gonza´lez, M. J. Org. Chem. 1996, 61, 8849. (b) Fustero,
S.; Navarro, A.; Asensio, A. Tetrahedron Lett. 1997, 38, 4891. Corri-
genda: Tetrahedron Lett. 1997, 38, 6477. (c) Fustero, S.; Navarro, A.; Pina,
B.; Asensio, A.; Bravo, P.; Crucianelli, M.; Volonterio, A.; Zanda, M. J.
Org. Chem. 1998, 63, 6210.
Scheme 1
(11) Fustero, S.; Pina, B.; Simo´n Fuentes, A. Tetrahedron Lett. 1997,
38, 6771.
(12) Several fluorine-containing amino acids have been used in the design
of protease and suicide inhibitors. See for example: Fluorine-containing
Amino Acids: Synthesis and Properties; Kukhar, V. P., Soloshonok, V.
A., Eds.; Wiley: Chichester, U.K., 1994.
(13) Kaneko, S.; Yamazaki, T.; Kitazume, T. J. Org. Chem. 1993, 58,
2302.
(14) Abouabdellah, A.; Be´gue´, J.-P.; Bonnet-Delpon, D.; Thanh Nga,
T. T. J. Org. Chem. 1997, 62, 8826 and literature cited therein.
(15) Uneyama, K.; Hao, J.; Amii, H. Tetrahedron Lett. 1998, 39, 4079.
978
Org. Lett., Vol. 1, No. 7, 1999

Table 2. R-Methyl â-Fluoroalkyl â-Amino Esters 4 and γ-Amino Alcohols 5 Obtained by Reduction of 3
entry 3a product 4 (5) yield (%) of 4b (syn/ anti)c yield (%) of 5b (syn/ anti)c
[H] reacn conditions
3a NaBH3CN THF-MeOH‚HCl (4:1), room temp, 4 h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4a
4a
90 (67/33)
90 (93/7)
43 (96/4)
32 (90/10)
90 (98/2)
73 (98/2)
70 (96/4)
92 (98/2)
71 (96/4)
86 (97/3)
99 (65/35)
98 (94/6)
82 (73/27)
30 (>95/5)
36 (97/3)
3a NaBH4
3a NaBH4
3a NaBH4
3a NaBH4
3a NaBH4
3a Zn(BH4)2
3b NaBH4
3c NaBH4
3c NaBH4
ZnBr2 (1.5 equiv), CH2Cl2, room temp, 20 h
ZnBr2 (1.5 equiv), CH2Cl2, ∆, 48 h
ZnCl2 (1.5 equiv), CH2Cl2, room temp, 48 h
ZnI2 (3.0 equiv), CH2Cl2, room temp, 24 h
ZnI2 (1.5 equiv), CH2Cl2, ∆, 8 h
7 (99/1)
57 (99/1)
4a (5a )
4a
4a (5a )
4a (5a )
4a (5a )
4b
4c
4c (5c)
4d
4d
4e
4e
4e (5e)
10 (99/1)
27 (99/1)
10 (99/1)
CH2Cl2, room temp, 24 h
ZnI2 (3.0 equiv), CH2Cl2, room temp, 48 h
ZnI2 (3.0 equiv), CH2Cl2, room temp, 24 h
ZnI2 (3.0 equiv), CH2Cl2, ∆, 24 h
10 (99/1)
3d NaBH3CN THF-MeOH‚HCl (4:1), room temp, 4 h
3d NaBH4 ZnI2 (3.0 equiv), CH2Cl2, ∆, 24 h
3e NaBH3CN THF-MeOH‚HCl (4:1), room temp, 5 h
3e NaBH4
3e NaBH4
ZnI2 (3.0 equiv), CH2Cl2, room temp, 24 h
ZnI2 (3.0 equiv), CH2Cl2, ∆, 48 h
20 (99/1)
a All reactions were carried out on a 2.0 mmol scale. b Yields of the crude mixture. Isolated yield: syn-4a (81%); syn-4b (81%); syn-4c (70%); syn-4d
(80%); syn-4e (30%). c The syn/anti diastereoisomer ratios for 4 and 5 were determined on the crude reaction mixtures by 19F NMR.
and NaBH(OAc)3 and catalytic hydrogenation (Pd/C) were
much less efficient with regard to chemical yield and
stereoselectivity.
fluoromethyl (3d) derivatives, resulted not only in a lower
chemical yield but also in an increasing amount of γ-amino
alcohol 5e (entries 14 and 15, Table 2).
Compounds 419 and 5 were easily separated by means of
flash chromatography, and they showed spectroscopic (1H,
13C, and 19F NMR), analytical, and/or HRMS data in
agreement with the proposed structure.20 Further corrobora-
tion for the correct configuration assignments for these
derivatives (4 or 5) was unambiguously obtained by X-ray
crystallographic analyses. Because we were unable to obtain
adequate single crystals for the major diastereoisomer
(2R*,3R*)-4, the relative stereochemistry of the two newly
chiral created centers was determined for the fluorinated
Next, we examined the use of sodium borohydride
(NaBH4) in the presence of different zinc halides as chelating
agents. The reactions were carried out in dry CH2Cl2 as the
solvent at room temperature, and the process worked
extremely well, providing mainly the syn R-methyl â-fluo-
roalkyl â-amino esters 4 in high yields and, in general, with
excellent diastereoselectivity (entries 5, 8, 10, 12, and 15 in
Table 2).
It is worth noting that, on some occasions, especially when
the reduction reaction was performed at higher temperature
and/or for long reaction times, we also observed the
formation of variable amounts of the corresponding γ-amino
alcohols 5, which were isolated almost exclusively as single
syn diastereoisomers (syn/anti ) 99/1) (Scheme 1 and Table
2).
(19) General Procedure for the Synthesis of R-Methyl â-Fluoroalkyl
â-Amino Esters 4. To a solution of anhydrous zinc iodide (1.91 g, 6.0
mmol) in dry CH2Cl2 (20 mL) at 0 °C was added the corresponding
R-methyl â-fluoroalkyl â-enamino ester 3 (2.0 mmol). The resulting mixture
was stirred at the same temperature for 1 h, and then NaBH4 (0.375 g, 10
mmol) was added, also at 0 °C. The solution was allowed to reach room
temperature and then monitored by means of TLC. The reaction mixture
was quenched with saturated ammonium chloride solution and extracted
with dichloromethane (3 × 20 mL). The organic layers were combined,
washed with brine, and dried over sodium sulfate. After filtration, the
solvents were removed under reduced pressure to provide the crude reaction
mixture 4 and/or 5. Purification was carried out as indicated in each case.
(2R*,3R*)-4b: flash chromatography (n-hexanes-EtOAc (7:1)) on silica
The best results were obtained by employing an excess
(3.0 equiv) of anhydrous ZnI2 as the chelating agent and CH2-
18
Cl2 as the solvent, as shown in Table 2. In contrast, other
zinc salts such as ZnBr2 (entry 2, Table 2) and, particularly,
ZnCl2 (entry 4, Table 2) were less effective. In addition, the
use of Zn(BH4)2 as the reducing agent instead of the system
ZnI2/NaBH4 yielded slightly lower diastereoisomeric ratios
and chemical yields (entry 7, Table 2). The replacement of
the methyl group in R2 by ethyl or tert-butyl groups did not
affect the stereoselectivity to a significant degree (entries
8-10, Table 2). However, the use of the pentafluoroethyl
species 3e, instead of trifluoromethyl (3a-c) or chlorodi-
1
gel (Rf ) 0.3) gave a yellow solid (81%); mp 40-42 °C; H NMR (400
MHz) 1.09 (t, J ) 8.7 Hz, 3H), 1.20 (d, J ) 4.4 Hz, 3H); 2.84 (m, 1H),
3.51 (br d, J ) 6.5 Hz, 1H), 3.64 (s, 3H), 3.40 (q, J ) 4.4 Hz, 2H), 4.30-
4.40 (m, 1H), 6.60 (d, J ) 5.7 Hz, 2H), 6.68 (d, J ) 5.6 Hz, 2H); 13C
NMR (100 MHz) 11.4 (q), 13.8 (q), 39.6 (d), 55.5 (q), 58.2 (q, 2JCF ) 28.1
1
Hz), 61.1 (t), 114.7 (d), 115.6 (d), 125.7 (q, JCF ) 283.0 Hz), 140.0 (s),
153.2 (s), 172.7 (s); 19F NMR (376 MHz) -73.5 (d, JFH ) 8.0 Hz); HRMS
calcd for C13H18F3NO3 305.1238, found 305.1251. Anal. Calcd for C13H18F3-
NO3: C, 55.08; H, 5.94; N, 4.59. Found: C, 55.10; H, 5.96; N, 4.57.
(20) Further conversion of 4 into the N-unprotected â-amino esters 6
has been carried out by standard procedures. Thus, for example, treatment
of 4b with ceric ammonium nitrate (CAN) in CH3CN-H2O (1:1) as the
solvent afforded to (2R*,3R*)-6 in 90% overall yield:
(16) (a) Soloshonok, V. A.; Soloshonok, I. V.; Kukhar, V. P.; Svedas,
V. K. J. Org. Chem. 1998, 63, 1878 and literature cited therein. For the
biocatalytic and enantioselective biomimetic version with R-unsubstituted
â-fluoroalkyl â-amino acids, see: (b) Soloshonok, V. A.; Soloshonok, I.
V.; Ono, T. J. Org. Chem. 1997, 62, 7538 and literature cited therein.
(17) Uneyama, K.; Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe,
H. J. Org. Chem. 1993, 58, 32.
(18) Others solvents such as diethyl ether (Et2O) or tetrahydrofuran (THF)
gave poorer results.
Org. Lett., Vol. 1, No. 7, 1999
979

γ-amino alcohol derivative (2R*,3R*)-5a,21 which was
obtained in excellent overall yield by means of LiAlH4/THF
reduction of the diastereomerically pure R-methyl â-trifluo-
romethyl â-amino ester 4a as outlined in Scheme 2. The
Scheme 2
Figure 1.
strategy to fluorinated â-amino esters will be convenient for
the enantioselective synthesis of these and other related
systems. Further studies along these lines are in progess.
stereochemical outcome of the reduction reaction of 3 to the
major diastereoisomer syn-4 can be easily understood if it
is assumed that hydride attacks the imino carbon from the
opposite side (si face) of the R-methyl group (ul-1,2-
addition), since ZnI2 coordinates with both ester carbonyl
oxygen and the nitrogen imino group in a six-membered
metal chelate (Figure 1).
In summary, the first effective diastereoselective synthesis
of syn R-methyl â-fluoroalkyl â-amino esters 4 and γ-amino
alcohols 5 by means of chemical reduction of the corre-
sponding â-enamino esters 3 has been developed. The
process works well, it is very simple and inexpensive, and
easily available starting materials are used. We feel this new
Acknowledgment. We thank the Direccio´n General de
Investigacio´n Cient´ıfica y Te´cnica (DGES PB97-0760-C02-
01) for financial support. B.P., M.G.T., and A.N. are indebted
to the Generalitat Valenciana, the Fundacio´n Ramo´n Areces,
and the Universidad de Valencia for predoctoral fellowships.
Supporting Information Available: Text giving spec-
troscopic data and experimental details for 3a-e, syn-4a-
e, anti-4a, 5a,e, and 6 and an ORTEP drawing of syn-5a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Full details of the X-ray structure of (2R*,3R*)-5a will be published
in a full account of this work.
OL990774O
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Org. Lett., Vol. 1, No. 7, 1999