New strategy for the stereoselective synthesis of fluorinated β-amino acids

Article abstract of DOI:10.1021/jo025621k

Racemic and chiral nonracemic α-substituted and α-unsubstituted β-fluoroalkyl β-amino acid derivatives 6 and 9 have been synthesized in two steps starting from fluorinated imidoyl chlorides 1 and ester enolates. This approach is based on the chemical reduction of previously obtained γ-fluorinated β-enamino esters 4 by using ZnI₂/NaBH₄ in a nonchelated aprotic medium (dry CH₂Cl₂) as the reducing agent. A metal-chelated six-membered model has been suggested to explain the stereochemical outcome of the reduction reaction. The process takes place with high yields and with moderate to good diastereoselectivity. The best results related to diastereoselective reduction of chiral β-enamino esters 4 were provided by the use of (-)-8-phenylmenthol as a chiral auxiliary.

Full text of DOI:10.1021/jo025621k

New Str a tegy for th e Ster eoselective Syn th esis of F lu or in a ted
â-Am in o Acid s
Santos Fustero,* Bele´n Pina, Esther Salavert, Antonio Navarro,
M. Carmen Ram´ırez de Arellano,† and Antonio Simo´n Fuentes
Departamento de Quı´mica Orga´nica, Facultad de Farmacia, Universidad de Valencia,
46100-Burjassot (Valencia), Spain
santos.fustero@uv..es
Received February 18, 2002
Racemic and chiral nonracemic R-substituted and R-unsubstituted â-fluoroalkyl â-amino acid
derivatives 6 and 9 have been synthesized in two steps starting from fluorinated imidoyl chlorides
1 and ester enolates. This approach is based on the chemical reduction of previously obtained
γ-fluorinated â-enamino esters 4 by using ZnI2/NaBH4 in a nonchelated aprotic medium (dry CH2-
Cl2) as the reducing agent. A metal-chelated six-membered model has been suggested to explain
the stereochemical outcome of the reduction reaction. The process takes place with high yields and
with moderate to good diastereoselectivity. The best results related to diastereoselective reduction
of chiral â-enamino esters 4 were provided by the use of (-)-8-phenylmenthol as a chiral auxiliary.
In tr od u ction
In addition, organofluorine chemistry is receiving
remarkable interest due to the enormous utility of
organofluorine compounds in several fields such as
medicinal, biological, agricultural, and analytical chem-
istry.5 In particular, fluorinated amino acids and amino
alcohols have been shown to demonstrate extensive
biological activity.2,3c,6
The synthesis and reactivity of 1,3-difunctionalized
derivatives represent an active area of investigation in
organic chemistry, especially those aspects related to the
stereoselective synthesis of â-amino acids.1 The special
value of these products is due to their potential thera-
peutic applications and to their use as valuable inter-
mediates in the design and construction of novel biologi-
cal and medicinally important molecules.2
Some free â-amino acids play an important role in the
biological activity of complex molecules. For example, the
anticancer activity of Taxol mainly depends on the
presence of an N-benzoyl-(2R,3S)-3-phenylisoserine moi-
ety in its framework.2,3 Furthermore, these compounds
are receiving increasing attention due to the fact that
â-peptides, constituted entirely by â-amino acid units as
opposed to R-amino acid units, are emerging as a class
of unnatural biopolymers that present interesting sec-
ondary structures, as well as increased potency and
enzymatic stability.2,4
Considering the benefits of fluorine substitution for
hydrogen, the development of new synthetic methodolo-
gies for preparing fluorine-containing enantiomerically
pure â-amino acids is of particular interest. There are
two main strategies that have been followed to synthesize
these products, the direct fluorination strategy and the
building block approach. Related to the former, the
synthesis of R-fluoro-â-amino acids from â-hydroxy-R-
amino acids has been described.7 Furthermore, Davis
(4) (a) Koert, U. Angew. Chem., Int. Ed. Engl. 1997, 36, 1836-1837.
(b) Applequist, J .; Bode, K. A.; Apella, D. H.; Christianson, L. A.;
Gellman, S. H. J . Am. Chem. Soc. 1998, 120, 4891-4892. (c) Clark, T.
D.; Buehler, L. K.; Ghadiri, M. R. J . Am. Chem. Soc. 1998, 120, 651-
656.
(5) See, for example: (a) Banks, R. E.; Tatlow, J . C.; Smart, B. E.
Organofluorine Chemistry: Principles and Commercial Applications;
Plenum Press: New York, 1994. (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)
Houben-Weyl Methods of Organic Chemistry: Organo-Fluorine Com-
pounds, Workbench ed.; Georg Thieme Verlag: Stuttgart, 2000; Vols.
E10a-c.
* To whom correspondence should be addressed.
† Corresponding author regarding X-ray diffraction studies.
(1) For reviews see: (a) Helmchen, G.; Hoffman, R. W.; Mulzer, J .;
Schaumann, E. Houben-Weyl Methods of Organic Chemistry: Stereo-
selective Synthesis, Workbench ed.; ; Georg Thieme Verlag: Stuttgart,
1996; Vol. E21. (b) Cole, D. Tetrahedron 1994, 50, 9517-9582. (c)
J uaristi, E.; Quintana, D.; Escalante, J . Aldrichimica Acta 1994, 27,
3-11. (d) Enantioselective Synthesis of â-Amino Acids; J uaristi, E., Ed.;
Wiley-VCH: New York, 1997. (e) J uaristi, E.; Lo´pez-Ruiz, H. Curr.
Med. Chem. 1999, 6, 983-1004.
(6) For reviews, see: (a) Fluorine-Containing Amino Acids: Syn-
thesis and Properties; Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley:
Chichester, UK, 1994. (b) Be`gue`, J .-P.; Bonnet-Delpon, D. Trifluorom-
ethylated Amino Alcohols: New Synthetic Approaches and Medicinal
Targets. In Biomedical Frontiers of Fluorine Chemistry; Ojima, I.,
McCarthy, J . R., Welch, J . T., Eds.; American Chemical Society:
Washington, DC, 1996; pp 59-72. (c) Enantiocontrolled Synthesis of
Fluoro-Organic Compounds; Soloshonok, V. A., Ed.; Wiley: Chichester,
UK, 1999. (d) Sutherland, A.; Wilis, C. L. Nat. Prod. Rep. 2000, 17,
621-631 and references cited therein.
(2) Reviews: (a) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996,
25, 117-128. (b) Hintermann, T.; Seebach, D. Chimia 1997, 51, 244-
247. (c) Scarborough, R. M. Curr. Med. Chem. 1999, 6, 971-982. (d)
Abdel-Magid, A. F.; Cohen, J . H.; Maryanoff, C. A. Curr. Med. Chem.
1999, 6, 955-970.
(3) Several distinct total syntheses of Taxol have been disclosed. See,
for example: (a) Winkler, J . D. Tetrahedron 1992, 48, 6953. (b) Nicolau,
K. C.; Guy, R. K. Angew. Chem., Int. Ed. Engl. 1995, 34, 2079-2090.
(c) Ojima, I.; Lin, S.; Wang, T. Curr. Med. Chem. 1999, 6, 927-954.
(7) Shanzer, A.; Smoekh, L. J . Am. Chem. Soc. 1982, 104, 5836-
5837.
10.1021/jo025621k CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/29/2002
J . Org. Chem. 2002, 67, 4667-4679
4667

Fustero et al.
SCHEME 1
reported the electrophilic R-fluorination of nonfluorinated
â-amino esters in moderate diastereoselectivity.8
However, most of the described processes for the
synthesis of fluorinated â-amino acids are based on the
use of the building block approach. Although several
synthetic routes to these derivatives have been reported,
most of them suffer various limitations related to the poor
diastereoselectivity observed. Be´gue´ described the
[2 + 2] cycloaddition between fluoroalkyl imines and
ketenes in order to access enantiopure methyl syn-CF3-
isoserinates.9 The same authors have very recently
reported a new strategy based on the reaction of ethyl
diazoacetate with CF3-imines, followed by ring-opening
of aziridine intermediates with various nucleophiles.10,11
On the other hand, strategies that imply the use of
reductive and chemoenzymatic approaches are less fre-
quent. Shen in 1995 obtained racemic â-amino acids by
catalytic hydrogenation starting from their precursors,
fluoroalkyl enamines.12 More recently, Uneyama de-
scribed the synthesis of racemic anti-â-trifluoromethyl
isoserine by diastereoselective reduction of R-hydroxy-â-
imino esters obtained via base-catalyzed intramolecular
rearrangement of imino ethers.13
Moreover, Soloshonok designed a chemoenzymatic
approach to synthesize â-fluoroalkyl-â-amino acids by
stereoselective biomimetic transamination of R-alkyl-â-
keto carboxylic esters, which implies a base catalyzed-
[1,3]-proton shift reaction followed by hydrolysis and
biocatalytic resolution by Penicillin acylasa. Alternative
procedures using chiral bases and chiral amines have also
been described.14
In the context of our ongoing study of the synthesis
and reactivity of 1,3-difunctionalized fluorine-containing
amino compounds,15 we have focused our attention on the
development of novel stereoselective reductive strategies
for the synthesis of enantiopure fluorinated â-amino acids
SCHEME 2
derivatives.16 Herein, we report an efficient two-step
route to prepare racemic and/or chiral nonracemic γ-flu-
orinated-â-amino acid derivatives through reductive
processes starting from fluorinated imidoyl halides 1 and
lithium enolate esters (Scheme 1).17
Resu lts a n d Discu ssion
Syn th esis of γ-F lu or in a ted â-En a m in o Acid De-
r iva tives 4 a n d 5. Fluorinated â-enamino esters 4 can
be prepared from fluorinated imidoyl chlorides 118 and
lithium enolates of alkyl esters, as is outlined in Scheme
2. Thus, the treatment of alkyl esters 2 (1.0 equiv) with
lithium diisopropylamide (LDA, 2.0 equiv) at -40 °C in
tetrahydrofuran (THF) for 2 h generated a slightly yellow
solution of the corresponding lithium enolate. Addition
of a variety of fluorinated N-alkyl or N-aryl-imidoyl
chlorides 1 (1.0 equiv) to this solution gave, after stan-
dard workup, γ-fluorinated-â-enamino esters 4 as the
only products. Table 1 summarizes the obtained results.
The scope of the process described above is illustrated
in Table 1. In general, the reaction works well, and good
to high yields (64-99%) are obtained regardless of the
nature of the starting materials 1 and 2. No excess of
the starting material is needed with the exception of the
base (LDA), for which a 2-fold excess of LDA is necessary.
The first equivalent is used to form the lithium ester
enolate, and the second is necessary in order to ensure
the presence of the intermediate 3, avoiding possible acid/
base side reactions and improving significantly the
chemical yield of the process (entries 2 and 8, Table 1)
as had already been postulated in related systems.19
Chiral fluorinated â-enamino esters can also be obtained
when starting from chiral esters20 (entries 10-14 and
21-22) or chiral imidoyl chlorides (entries 8 and 9).
(8) (a) Davis, F. A.; Reddy, R. E. Tetrahedron: Asymmetry 1994, 5,
955-960. (b) Davis, F. A.; Zhou, P.; Chen, B.-Ch. Chem. Soc. Rev. 1998,
27, 13-18.
(9) (a) Abouabdellah, A.; Be´gue´, J .-P.; Bonnet-Delpon, D. Synlett
1996, 399-400. (b) Abouabdellah, A.; Be´gue´, J .-P.; Bonnet-Delpon, D.;
Nga, T. J . Org. Chem. 1997, 62, 8826-8833.
(10) Crouse, B.; Narizuka, S.; Bonnet-Delpon, D.; Be´gue´, J .-P.
Synlett 2001, 679-681.
(11) Other examples, including Mannich-type reactions and Michael
additions, have also been reported. See, for example: (a) Kaneko, S.;
Yamazaki, T.; Kitazume, T. J . Org. Chem. 1993, 58, 2302-2312. (b)
Takaya, J .; Kagoshima, H.; Akiyama, T. Org. Lett. 2000, 2, 1577-1559.
(c) Ojima, I.; Kato, K.; Nakahashi, K.; Fuchikami, T.; Fujita, M. J .
Org. Chem. 1989, 54, 4511-4522. (d) Volonterio, A.; Bravo, P.; Zanda,
M. Org. Lett. 2000, 2, 1827-1830. (e) Volonterio, A.; Bravo, P.;
Moussier, N.; Zanda, M. Tetrahedron Lett. 2000, 41, 6517-6521.
(12) Cen, W.; Ni, Y.; Shen, Y. J . Fluorine Chem. 1995, 73, 161-
164.
(13) Uneyama, K.; Hao, J .; Amii, H. Tetrahedron Lett. 1998, 39,
4079-4082.
(14) (a) Soloshonok, V. A.; Kirilenko, A. G.; Kukhar, V. P.; Galushko,
S. Tetrahedron Lett. 1994, 34, 5063-5066. (b) Soloshonok, V. A.; Ono,
T.; Soloshonok, I. V. J . Org. Chem. 1997, 62, 7538-7539. (c) Solos-
honok, V. A.; Svedas, V. K.; Kukhar, V. P.; Kirilenko, A. G.; Rybakova,
A. V.; Solodenko, V. A.; Fokina, N. A.; Kogut, O. V.; Galaev, I. Y.;
Kozlova, E. V.; Shishkina, I. P.; Galushko, S. V. Synlett 1993, 339-
341. (d) Soloshonok, V. A.; Soloshonok, I. V.; Kukhar, V. P.; Svedas,
V. K. J . Org. Chem. 1998, 63, 1878-1884.
(16) Fustero, S.; Salavert, E.; Pina, B.; Ram´ırez de Arellano, C.;
Asensio, A. Tetrahedron 2001, 57, 6475-6486.
(15) (a) Fustero, S.; Garc´ıa del la Torre, M.; J ofre´, V.; Pe´rez Carlo´n,
R.; Navarro, A.; Simo´n Fuentes, A.; Server Carrio´, J . J . Org. Chem.
1967, 32, 8825-8836. (b) Fustero, S.; Navarro, A.; Pina, B.; Asensio,
A.; Bravo, P.; Crucianelli, M.; Volonterio, A.; Zanda, M. J . Org. Chem.
1998, 63, 6210-6219. (c) Fustero, S.; Garc´ıa de la Torre, M.; Pina, B.;
Simo´n Fuentes, A. J . Org. Chem. 1999, 64, 5551-5556. (d) Fustero,
S.; D´ıaz, M. D.; Navarro, A.; Salavert, E.; Aguilar, E. Tetrahedron 2001,
57, 703-712.
(17) (a) Fustero, S.; Pina, B.; Simo´n Fuentes, A. Tetrahedron Lett.
1997, 38, 6771-6774. (b) Fustero, S.; Pina, B.; Garc´ıa de la Torre, M.;
Navarro, A.; Ram´ırez de Arellano, C.; Simo´n Fuentes, A. Org. Lett.
1999, 1, 977-980.
(18) Uneyama, K.; Tamura, K.; Mizukami, H.; Maeda, K. J . Org.
Chem. 1993, 58, 32-36.
(19) (a) Huang, W. S.; Yuan, C. Y. J . Chem. Soc., Perkin Trans. 1
1995, 741-742. (b) See also refs 15 and 16.
4668 J . Org. Chem., Vol. 67, No. 14, 2002

Stereoselective Synthesis of Fluorinated â-Amino Acids
TABLE 1. F lu or in a ted â-En a m in o Ester s 4 Obta in ed fr om Im id oyl Ch lor id es 1 a n d Ester s 2
a
b
19
All reactions were carried out on an 8.0 mmol scale. Imino/enamino tautomer ratio estimated by 1H and
F NMR on the crude
mixture. c Isolated yield. Yield using 1.0 equiv of LDA.
d
Table 1 also shows that products 4 are, in general,
isolated as a mixture of imino (4I) and enamino (4E)
tautomers. The ratio 4I/4E is influenced by the length
of the perfluoroalkyl chain.21 In general, it is observed
that the longer the perfluoroalkyl substituent, the higher
the ratio of imino tautomer; however, this tautomer was
never isolated as the unique tautomer, opposite to the
enamino tautomer form (see, for example, entries 4, 6,
9, 11, 12, and 14, Table 1).
The configuration of the enamino double bond in
tautomer 4E (Figure 1) was also studied. NMR analyses
(1H, 19F, 13C) at room temperature showed that only one
of the two possible geometric isomers occurs. The down-
field chemical shift of the N-H proton (see Experimental
J . Org. Chem, Vol. 67, No. 14, 2002 4669

Fustero et al.
SCHEME 4
F IGURE 1.
SCHEME 3
Ch em o- a n d Ster eoselective Red u ction of γ-F lu -
or in a ted â-En a m in o Acid Der iva tives. In general, the
chemoselective reduction of â-enamino acid derivatives
is a simple and attractive route to â-amino acids.1d,24
There are, however, several problems related with the
chemo- and stereoselectivity that have limited the de-
velopment of efficient reductive processes. In fact, to the
best of our knowledge, only two reports regarding the
synthesis of racemic γ-fluorinated â-amino acids whose
key step involves the use of reductive methods have been
described.12,13
To develop an effective process in terms of yield and
chemo- and stereoselectivity to synthesize enantiopure
fluorinated â-amino acids 9, we first addressed the study
of the reduction of fluorinated â-enamino esters 4 to the
corresponding â-amino derivatives 6 (Scheme 4 and
Tables 2 and 4).
We first carried out the reduction in different reaction
conditions (Table 2). Table 2 shows a variety of reducing
agents, solvents, and temperatures that were studied to
produce â-fluoroalkyl â-amino esters 6. Thus, sodium
borohydride derivatives such as sodium cyanoborohy-
dride (NaCNBH3) in a 4:1 mixture of THF and methan-
olic HCl as a solvent at room temperature provided high
chemical yields of fluorinated â-amino esters 6; in
R-substituted derivatives (R3 * H) (entries 8-25, Table
2), a separable syn/anti mixture was obtained, although
only moderate diastereoselectivity (de 30-46%) was
observed (see entries 8, 20, and 22, Table 2).25
We next examined the behavior of sodium borohydride
(NaBH4) in a nonchelated aprotic medium (dry CH2Cl2)
along with the effect of the presence of different anhy-
drous zinc halides as chelating agents. The reactions were
performed at room temperature and gave (()-syn-R-alkyl-
â-fluoroalkyl-â-amino esters 6 with high yields (90%) and
excellent diastereoselectivity (de up to 96%).26
From this study, the best diastereoselectivity was
obtained using an excess of anhydrous ZnI2 (3.0 equiv)
and NaBH4 (5.0 equiv) in dry dichloromethane at room
temperature for 24 h (see, for example, entry 12, Table
2).27 Other solvents such as diethyl ether (entry 13, Table
Section) is typical of a hydrogen bond with the carbonyl
group oxygen, therefore suggesting a chelated configu-
ration, Z, s-cis (Figure 1). To confirm this hypothesis, a
2D HOESY NMR 1H-19F experiment was carried out.
For 4a , this analysis showed (entry 1, Table 1) a cross-
peak between the CF3 moiety (δ -63.8, 19F NMR) with
the vinylic hydrogen (δ 5.28 ppm,1H NMR).22
Similarly, the scope of the reported approach has also
been successfully extended to the synthesis of other
â-enamino acids derivatives, such as fluorinated â-enam-
ino amides 5a -d derived from chiral nonracemic acyclic
and cyclic amides (Scheme 3). Thus, fluorinated imidoyl
chloride 1a (RF ) CF3, R1 ) p-MeOC6H4) reacts with a
range of chiral amides,23 under the same conditions as
described above, to exclusively provide the enamino
tautomers 5a -d in generally good yields.
(20) Chiral esters have been obtained by acetylation (Ac2O/Py) of
the corresponding alcohols. See, for example: (a) Ort, O. Org. Synth.
1987, 65, 203-213. (b) D’Angelo, J .; Maddaluno, J . J . Am. Chem. Soc.
1986, 108, 8112-8114. (c) Commins, D. L.; Salvador, J . M. J . Org.
Chem. 1993, 58, 4656-4661. (d) 8-(4-Iodo)phenylmenthol acetate was
prepared by regioselective aromatic iodation of 8-phenylmenthol
acetate with commercially available bis(pyridine)iodonium(I) tetrafluo-
roborate (IPy2BF4). See, for example: Barluenga, J .; Gonza´lez, J . M.;
Garc´ıa-Mart´ın, M.; Campos, P. J .; Asensio, G. J . Org. Chem. 1993, 58,
2058-2060.
(21) Portella, C.; Iznaden, M. Tetrahedron Lett. 1988, 29, 3683-
3686.
(22) The signal connecting the fluorine atoms with the hydrogen of
the p-anisidin ring at δ 7.15 ppm unequivocally corroborates the
Z-configuration of the enamino tautomer 4b.
(23) While (S)-3-acetyl-4-benzyl-2-oxazolidinone is commercially
available, (1S)-N-acetyl-2,10-camphorsultam was prepared by treat-
ment of camphor sultam with Ac2O/Py. In the same way, γ-lactams
providing 5c and 5d were obtained in three steps from L-pyroglutamic
acid following procedures described in the literature. See: (a) Otsuka,
M.; Takeshi, M.; Haupt, A.; Ohno, M.; Shiraki, T.; Sugiura, Y.; Maeda,
K. J . Am. Chem. Soc. 1990, 112, 838-845. (b) Kocienski, P. J . In
Protecting Groups; Georg Thieme Verlag: Stuttgart, 1994; Chapter 6,
p 224.
(24) (a) Palmieri, M.; Bartoli, G.; Cimarelli, C.; Marcantoni, E.;
Petrini, G. J . Org. Chem. 1994, 59, 5328-5335. (b) Palmieri, M.;
Cimarelli, C. J . Org. Chem. 1996, 61, 5557-5563.
(25) Other reducing agents such as L-Selectride, n-Bu4NBH4, NaBH-
(OAc)3, DIBALH, and catalytic hydrogenation (Pd/C) were much less
efficient with regard to chemical yield and stereoselectivity.
(26) Only in some instances, especially when higher temperatures
and/or reaction times where used, were variable amounts of the
corresponding γ-amino alcohols 7, isolated mainly as syn isomers,
detected.
4670 J . Org. Chem., Vol. 67, No. 14, 2002

Stereoselective Synthesis of Fluorinated â-Amino Acids
TABLE 2. Ra cem ic â-F lu or oa lk yl â-Am in o Ester s 6 a n d γ-Am in o Alcoh ols 7 Obta in ed by Red u ction of 4
entry
4a
[H]
reaction conditions
product 6 (7)
yield (%) of 6b (syn/anti)
yield (%) of 7c (syn/anti)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4a
4a
4b
4e
4f
4i
NaBH3CN
NaBH4
NaBH4
NaBH3CN
NaBH3CN
NaBH3CN
NaBH4
NaBH3CN
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
Zn(BH4)2
NaBH4
NaBH4
NaBH4
NaBH4
NaBH3CN
NaBH4
NaBH3CN
NaBH4
NaBH4
THF-AcOH, D, 24 h
6a
6a
6b
6c
6d
6e
6e
6f
6f (7a )
6f (7a )
6f
6f (7a )
6f (7a )
6f (7a )
6f (7a )
6g
6h
6i
6i (7a )
6j
6j
70
98
99
98
THF-MeOH, 0 °C, 1.5 h
THF-MeOH, 0 °C, 2 h
THF-MeOH-HCl (4:1), 0 °C, 0.5 h
THF-MeOH-HCl (4:1), 0 °C, 1.5 h
THF-MeOH-HCl (4:1), 0 °C, 1.5 h
ZnI2 (3.0 equiv), CH2Cl2, rt, 15 h
THF-MeOH-HCl (4:1), rt, 4 h
ZnBr2 (1.5 equiv), CH2Cl2, rt, 20 h
ZnBr2 (1.5 equiv), CH2Cl2, D, 20 h
ZnCl2 (1.5 equiv), CH2Cl2, rt, 48 h
ZnI2 (3.0 equiv), CH2Cl2, rt, 24 h
ZnI2 (3.0 equiv), Et2O, rt, 24 h
ZnI2 (1.5 equiv), CH2Cl2, ∆, 8 h
CH2Cl2, rt, 24 h
90
98 (45/55)d
50 (45/55)d
90 (67/33)
90 (93/7)
43 (96/4)
32 (90/10)
90 (98/2)
18 (83/17)
73 (98/2)
70 (96/4)
94 (95/5)
92 (98/2)
71 (96/4)
86 (97/3)
99 (65/35)
98 (94/6)
82 (73/27)
30 (>95/5)
36 (97/3)
4i
4o
4o
4o
4o
4o
4o
4o
4o
4p
4q
4r
4r
4s
4s
4t
7 (99/1)
57 (99/1)
10 (99/1)
30 (89/11)
27 (99/1)
10 (99/1)
ZnI2 (3.0 equiv), CH2Cl2, rt, 24 h
ZnI2 (3.0 equiv), CH2Cl2, rt, 48 h
ZnI2 (3.0 equiv), CH2Cl2, rt, 24 h
ZnI2 (3.0 equiv), CH2Cl2, ∆, 24 h
THF-MeOH‚HCl (4:1), rt, 4 h
ZnI2 (3.0 equiv), CH2Cl2, ∆, 24 h
THF-MeOH‚HCl (4:1), rt, 5 h
ZnI2 (3.0 equiv), CH2Cl2, rt, 24 h
ZnI2 (3.0 equiv), CH2Cl2, ∆, 24 h
ZnI2 (3.0 equiv), PhCH3, ∆, 24 h
10 (99/1)
6k
6k
6k (7b)
d
4t
4t
4t
20 (99/1)
NaBH4
a
b
All reactions were carried out on a 2.0 mmol scale. Yields of the crude mixture. c Syn/anti diastereomer ratios for 6 and 7 were
determined on crude reaction mixtures by 1H and 19F NMR. Complex mixture.
d
TABLE 3. Ch ir a l γ-F lu or in a ted â-Am in o Ester s 6
Obta in ed by Red u ction of 4
TABLE 4. â-Am in o Ester s 6 Obta in ed by Ma n n ich
Rea ction w ith F lu or in a ted Im in es 8
yielda
syn/ antib
(S)-6a /(R)-6bb
entry
R2
(%) (R3 ) Me) (6f) (R3 ) H) (6m )
1
2
Me
(-)-8-phenylmenthol
38
58
36/64
31/69
a
b
Isolated yield of the diastereomeric mixture. Syn/anti and
R/â diastereomer ratio was determined on crude reaction mixtures
by 19F NMR.
The effect of the RF, R2, and R3 substituens on the
diastereoselectivity was also examined. Thus, replace-
ment of the methyl group in the ester function by ethyl
or tert-butyl did not improve the diastereoselectivity of
the process to any significant degree (entries 12, 17, 18,
Table 2). In the same way, no significant effect was
observed when the methyl substituent in R3 was replaced
by an ethyl group (entry 16, Table 2). On the other hand,
we found that the reduction of 4t bearing a pentafluo-
roethyl group with NaBH4/ZnI2 resulted in not only a
lower chemical yield but also an increasing amount of
the nondesired γ-amino alcohol 7 (entries 23 and 24,
Table 2). In addition, the use of Zn(BH4)2 as a reducing
agent did not improve the chemical yield or the diaste-
reoselectivity (see entry 15 vs 12, Table 2).
a
b
In all cases, R1 ) p-MeOC6H4 (PMP) and R3 ) H. Reducing
conditions: ZnI2 (3.0 equiv), NaBH4 (5.0 equiv), dry CH2Cl2, rt.
c All reactions were carried out on a 2.0 mmol scale. R/â diaste-
d
Compounds 6 and 7 were separated and purified by
flash chromatography, and their structures were cor-
roborated by spectroscopic analyses (1H, 19F, and 13C
reomer ratio for 6 was determined on crude reaction mixtures by
1H and 19F NMR. e Yield of the crude reaction mixture.
2) and toluene (entry 25, Table 2) provided much less
efficient results.
(27) Other zinc halides salts such as ZnCl2 (entry 11, Table 2) and
ZnBr2 (entry 9, Table 2) were less effective.
J . Org. Chem, Vol. 67, No. 14, 2002 4671

Fustero et al.
F IGURE 2. (A) Packing diagrams of (2R*,3R*)-7a showing two linear chains formed through N-H‚‚‚O hydrogen bonds [N-H(1N)‚
‚‚O(1)#2 (#2: x - 1, y, z) 155(4)°, H(1N)‚‚‚O(1)#2 2.35(3), and N...O(1)#2 3.144(6) Å] and self-assembled through O-H‚‚‚O hydrogen
bonds [O(1)-H(1O)‚‚‚O(2)#1 (#1: x + 1/2, -y + 1/2, -z + 1) 174(8)°, H(1O)‚‚‚O(2)#1 1.99(2), and O(1)‚‚‚O(2)#1 2.796(6) Å]. (B)
View along the a-axis showing the tubular superstructure with C-H‚‚‚F hydrogen bonds [C(5)-H(5A)‚‚‚F(2)#3 (#3: -x + 1, y -
1/2, -z + 1/2) 125.8°, H(5A)‚‚‚F(2)#3 2.69, and C(5)‚‚‚F(2)#3 3.345(7) Å].
SCHEME 5
NMR). The relative stereochemical assignment was
performed over the fluorinated derivative γ-amino alcohol
F IGURE 3.
7a obtained easily from the reduction of the correspond-
ing major diastereomer 6f using LiAlH4 in a solution of
THF at room temperature (Scheme 5).
For this purpose, several chiral γ-fluorinated â-enam-
ino esters 4 (entries 8-14, 21, 22, Table 1) and â-enamino
amides 5 (Scheme 3) were examined. However, the use
of 2-benzyl-2-oxazolidinone and Oppolzer’s camphor sul-
tam as chiral auxiliaries (compounds 5a and 5b, respec-
tively) was disappointing, providing either a complex
mixture of products (starting from 5b) or a moderate
chemical yield with poor asymmetric induction in a
nonseparable mixture of diastereoisomers in the case of
5a . In the same way, derivatives 4 bearing the chiral
auxiliary group at the nitrogen atom like (S)-methyl
benzylamine (entry 9, Table 1) also gave a nonseparable
mixture of diastereoisomers (50%, de 10%) as indicated
by 19F NMR spectroscopy of the crude mixture.
For this reason, the study was then centered on the
reduction of systems bearing a chiral auxiliary in the
ester moiety. Thus, we chose chiral auxiliaries derived
from the same chiral source, (R)-pulegone,20 such as (-)-
8-phenylmenthol, (-)-8-(2-naphthyl)menthol, and (-)-8-
(4-iodo)phenylmenthol as well as, for the sake of com-
parison, (-)-menthol. The reduction of the corresponding
â-enamino esters 4j-n was carried out as described
above and provided cleanly chiral â-amino esters 6 in
good yield as a mixture of two diastereoisomers 6a and
6b (de up to 60%) (Table 3). Surprisingly, no essential
differences related to stereocontrol were observed for the
pulegone derivatives used (see, for example, entry 2 vs
entry 5, Table 3),29 compound 6m (entry 2, Table 3) being
the best result, for which a 4:1 R/â ratio was attained.
X-ray crystallographic analysis of the γ-amino alcohol
7a unambiguously assigned the configuration of C(2),C-
(3) as 2R*,3R*. The methyl group bonded to C(2) adopts
an anti conformation with respect to both the hydroxyl
group and the proton of the vicinal carbon atoms C(1)
and C(3), respectively. The amino group acts as a
hydrogen bond donor to the hydroxyl oxygen atom of a
different molecule [N-H(1N)‚‚‚O(1)#2] forming infinite
linear chains along the a-axis. The self-assembly of two
linear chains related by a screw axis through hydrogen
bonds between the hydroxyl group and the methoxyl
oxygen atom [O(1)-H(1O)‚‚‚O(2)#1] produces a tubular
superstructure28 (Figure 2). A C(5)-H(5A)‚‚‚F(2)#3 hy-
drogen bond is the closest contact between the nanotubes.
The stereochemical outcome of the reduction reaction
of compounds 4 (R3 * H) to the major diastereoisomer
syn-6 can easily be understood by assuming a cyclic
model in which the ZnI2 coordinates to the ester carbonyl
oxygen and to the nitrogen imino group in a six-
membered metal chelate. The hydride then attacks the
imino double bond from the opposite side (si face) to the
R-alkyl group (ul-1,2-addition) (Figure 3).
Considering the good results obtained in the diaste-
reoselective reduction of 4, we next envisaged applying
the optimal reduction conditions to the synthesis of chiral
nonracemic γ-fluorinated â-amino esters 6 (Table 3).
(28) Philip, D.; Stoddart, J . F. Angew. Chem., Int. Ed. Engl. 1996,
35, 1154-1196.
(29) For related non-fluorinated systems, see: Potin, D.; Dumas, F.;
d’Angelo, J . J . Am. Chem. Soc. 1990, 112, 3483-3486.
4672 J . Org. Chem., Vol. 67, No. 14, 2002

Stereoselective Synthesis of Fluorinated â-Amino Acids
SCHEME 7
F IGURE 4.
SCHEME 6
SCHEME 8
Isomers 6m r and 6m â were isolated in the pure form
as oily compounds by column chromatography on silica
gel. Their structures were ascertained by NMR (1H, 13C,
and 19F) spectroscopy analysis and by HRMS. The
absolute configuration of the newly created stereogenic
center at C(3) for the major diastereomer was established
as (S)-6m R through chemical correlation. This was made
by comparison of the [R] absolute values of the γ-amino
alcohol (-)-7c {[R]25D -53.2 (c 1.03, CHCl3)} obtained by
LAH reduction from the major isomer 6m r and the
known compound (+)-7c {[R]25 +52.4 (c 0.98, CHCl3)}.
D
Compound (+)-7c was alternatively prepared in two steps
from the previously described16 γ-fluorinated â-amino-
2
D -oxazoline (R)-8, in which the absolute stereochemistry
was ascertained by X-ray diffraction studies (Scheme 6).
The absolute configuration of 6m as 3S was extended to
the rest of â-amino esters 6n -p (Table 3).
The stereochemical outcome of the reduction of chiral
â-enamino esters 4k -n might be understood on the basis
of a cyclic model similar to the one described above in
which the hydride attack (re-face) is now conditioned by
the presence of the 8-phenyl group of the chiral auxiliary
(1,5-asymmetric induction), which effectively shields the
si-face of the Zn(II)-4 complex (Figure 4).
Finally, we examined the diastereoselective reduction
of the R-methyl γ-fluorinated â-enaminoester (-)-4v. In
this case, two new stereogenic centers are created at C(2)
and C(3), so four diastereomers are possible (Scheme 7).
The NMR analysis from the crude reduction mixture
showed that only three compounds were detected in a
ratio of 78/18/4. The syn diastereomers (2R,3R,R*)-6q
and (2S,3S,R*)-6q (overall 96% of the crude reaction
mixture) were isolated and purified by silica gel flash
chromatography as white solids; however, only from the
minor diastereomer were we able to obtain suitable
crystals, and the X-ray diffraction analysis results re-
vealed that this compound was (2S,3S,R*)-6q.
converted into the known γ-amino alcohol 7a (Scheme
8). Spectroscopic properties of the obtained product were
identical with the racemic version described above (see
Scheme 5), but the [R] value indicated that both are
enantiomers. Therefore, the absolute configuration of the
major syn diastereomer is (2R,3R,R*)-6q.
In this case, the stereochemical outcome could be
explained assuming the participation of two diastereo-
meric chelate models (Figure 5). Model A allowed us to
explain the formation of the major (2R,3R,R*)-6q dias-
tereomer by hydride attack from the opposite side to the
methyl group (si-face), whereas model B, which is by far
less stable due to steric hindrance between the methyl
and phenyl groups, provided the minor (2S,3S,R*)-6q
diastereomer (re-face hydride attack).
From the experimental results we concluded not only
that model A was predominant but also that the R3 group
(R3 ) Me for 6q) controls the hydride attack (1,2-
asymmetric induction) more than the presence of the
chiral auxiliary (1,5-asymmetric induction).
To further confirm the absolute configuration of the
major syn diastereomer, both isomers were separately
Parallel to this study, and for the sake of comparison,
we explored an alternative one-step method for the
J . Org. Chem, Vol. 67, No. 14, 2002 4673

Fustero et al.
SCHEME 10
Ti(i-PrO)4 in refluxing 2-propanol for 14 days cleanly gave
the corresponding isopropyl â-amino ester (S)-(+)-6a in
excellent yield (>95%) isolated as a yellowish solid; (-)-
8-phenylmenthol was recovered by flash chromatography
in ca. 91% yield (Scheme 10).
In summary, a new and effective method for the
diastereoselective synthesis of γ-fluorinated â-amino acid
derivatives 6 and 9 has been developed starting from
imidoyl halides 1, by means of chemical reduction. In
general, the process works well and allows the prepara-
tion of enantiopure R-substituted and R-nonsubstituted
â-fluoroalkyl â-amino esters 6 in a short, highly efficient
way by using (-)-8-phenylmenthol as a chiral auxiliary.
The use of ZnI2 as a Lewis acid in a nonchelated aprotic
medium (dry CH2Cl2) is the key step of the strategy to
yield the desired products in a diastereoselective manner.
A 1,2- more than a 1,5-asymmetric induction has been
suggested to explain the stereochemical outcome of the
reduction reaction in the case of chiral nonracemic
R-substituted â-enamino esters 4. Alternative and less
efficient strategies have also been tested.
F IGURE 5.
SCHEME 9
preparation of the title compounds 6, consisting in the
Mannich-like addition of lithium enolates of esters 2 to
trifluoromethyl imines 8 (Table 4).11 Two representative
examples were used in this study, as it is shown in Table
4. Thus, treatment of imine 8 with lithium enolate of
methyl propionate 2 (R2, R3 ) Me) led to a racemic
mixture of â-amino esters 6f in low yield with moderate
anti diastereoselectivity (de 28%) (entry 1, Table 4). On
the other hand, the use of a chiral ester 2 [R2 ) (-)-8-
phenylmenthyl; R3 ) H] did not provide much better
results with regard to chemical yield and diastereoselec-
tivity (entry 2, Table 4). Therefore, although the above-
mentioned reaction represents an alternative to the
reduction of â-enamino esters 4, the greater effectiveness
of the latter makes it the procedure of choice for the
diastereoselective synthesis of fluorinated â-amino esters
6.
Syn th esis of γ-F lu or in a ted â-Am in o Acid s 9. Fur-
ther conversion of 6 into â-amino acids 9 has been carried
out using a standard two-step sequence (Scheme 9). For
this purpose, selected examples were chosen. For racemic
6g and 6h , selective deprotection of the p-methoxyphenyl
group was easily achieved with cerium ammonium
nitrate (CAN) in CH3CN-H2O (2:1) at room temperature.
The crude N-unprotected â-amino esters without isolation
were then transformed into the desired â-amino acids 9
by acidic hydrolysis (6 N HCl) at 50 °C for 2 h. Isolation
and purification of the free racemic â-amino acids 9 were
achieved by means of ion-exchange chromatography
(DOWEX-50, H+ form).
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were run under an argon
atmosphere. Solvents were dried and distilled using standard
procedures before use. Chiral esters were prepared by con-
ventional procedures.20 Imidoyl chlorides 118 and trifluorom-
ethyl imines 811a were prepared according to the methods
described in the literature. All other reagents were of the best
commercial grade available and used without further purifica-
tion. Thin-layer chromatography (TLC) was performed with
UV active silica gel 60 F254, and the plates were visualized
with UV light and iodine. Flash column chromatography was
carried out using silica gel 60 (0.040-0.063 mm). Melting
points were uncorrected. All NMR spectra were recorded in
CDCl3 solution. 1H and 13C nuclei were determined using TMS
(0 ppm) and the center line of the chloroform-d triplet (77.0
ppm) as the internal standard, respectively, while CFCl3 (0
ppm) was used as the external standard for 19F nuclei. J values
are reported in hertz. Compositions of tautomeric and dias-
teromeric mixtures were established on the basis of 19F NMR
analysis. High-resolution mass spectra (HRMS) were obtained
at 70 eV by electron impact. FAB mass spectra were obtained
using Cs+ as reagent ions with a m-nitrobenzyl alcohol (NOBA)
matrix.
Gen er a l P r oced u r e for th e Syn th esis of â-F lu or oa lk yl
â-En a m in o Ester s 4. To a stirred solution of diisopropylamine
(2.24 mL, 16.8 mmol) in THF (10 mL) at -30 °C was added
n-butyllithium (2.5 M in hexane, 6.4 mL, 16.0 mmol) dropwise.
After the reaction mixture was stirred for 30 min, the solution
was cooled to -50 °C and alkyl ester 2 (0.91 mL, 8.0 mmol) in
THF (10 mL) was added dropwise. The resulting mixture was
stirred at -50 °C for 1.5 h and cooled to -78 °C. A solution of
the corresponding imidoyl chloride 1 (8.0 mmol) in THF (10
mL) was then slowly added. The reaction mixture was moni-
tored by TLC analysis, and after the total disappearance of
the starting material (TLC), the solvents were removed under
reduced pressure. The reaction was quenched with saturated
Finally, removal of the chiral auxiliary was carried out
by titanium(IV) isopropoxide-catalyzed transesterifica-
tion to isopropyl esters.30 Thus, treatment of 6m R with
(30) Sarakinos, G.; Corey, E. J . J . Org. Lett. 1999, 1, 1741-1744
and references cited therein. See also: Seebach, D.; Hungerbu¨ler, E.;
Naef, R.; Schnurrenberger, P.; Widmann, B.; Zu¨ger, M. Synthesis 1982,
138-141.
4674 J . Org. Chem., Vol. 67, No. 14, 2002

Stereoselective Synthesis of Fluorinated â-Amino Acids
3
ammonium chloride solution, and the mixture was extracted
with methylene chloride (2 × 25 mL). The combined organic
layers were dried over anhydrous sodium sulfate. Filtration
and evaporation of the solvent furnished the crude products
4, which were purified by flash silica gel column chromatog-
raphy as indicated for each example.
CDCl3) δ 21.9 (q), 24.9 (q), 53.8 (d), 67.0 (d), 85.9 (q, J CF
)
1
5.5 Hz), 120.2 (q, J CF ) 277.0 Hz), 125.3 (d), 127.2 (d), 128.6
(d), 143.9 (s), 147.5 (q, J CF ) 31.3 Hz), 169.5 (s); 19F NMR
2
(235 MHz, CDCl3) δ -66.4 (s, 3F); HRMS calcd for C15H18F3-
NO2 301.1289, found 301.1287. Anal. Calcd for C15H18F3NO2:
C, 59.80; H, 5.98; N, 4.65. Found: C, 59.93; H, 5.95; N, 4.61.
Isop r op yl 4,4,4-Tr iflu or o-3-(4-m et h oxya n ilin o)-2-b u -
ten oa te (4a ). Flash chromatography [n-hexane/EtOAc (5:1)]
on silica gel gave a yellow oil (85%). (Z)-Enamino tautomer:
1H NMR (250 MHz, CDCl3) δ 1.20 (d, J ) 6.2 Hz, 6H), 3.70 (s,
3H), 4.94-5.04 (m, 1H), 5.17 (s, 1H), 6.75 (d, J ) 8.5 Hz, 2H),
7.0 (d, J ) 8.7 Hz, 2H), 9.58 (brs, 1H); 13C NMR (62.8 MHz,
(+)-(2S,5S,1R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)-cy-
cloh exyl (Z)-4,4,4-Tr iflu or o-3-(4-m eth oxya n ilin o)-2-bu -
t en oa t e (4k ). Flash chromatography [n-hexane/AcOEt (30:
1)] on silica gel gave a yellow oil (72%): [R]25 +64.9 (c 1.04,
D
CHCl3); 1H NMR (250 MHz, CDCl3) δ 0.76-1.99 (m, 17H), 3.83
(s, 3H), 4.62 (s, 1H), 4.85 (td, J 1 ) 10.6 Hz, J 2 ) 4.3 Hz, 1H),
6.84-7.33 (m, 9H), 9.61 (brs, 1H); 13C NMR (62.8 MHz, CDCl3)
δ 21.8 (q), 25.3 (d), 26.5 (t), 27.4 (d), 31.3 (q), 34.5 (t), 39.6 (s),
41.8 (t), 50.6 (d), 55.3 (q), 73.9 (d), 88.1 (q, 3J CF ) 5.3 Hz), 113.9
3
CDCl3) δ 21.8 (q), 55.2 (q), 67.2 (d), 87.5 (q, J CF ) 5.6 Hz),
113.8 (d), 120.4 (q, 1J CF ) 277.0 Hz), 128.1 (d), 130.8 (s), 147.6
(q, 2J CF ) 30.5), 158.3 (s), 169.3 (s); 19F NMR (235 MHz, CDCl3)
δ -64.0 (s, 3F); HRMS calcd for C14H16F3NO3 303.1089, found
303.1089. Anal. Calcd for C14H16F3NO3: C, 55.52; H, 5.28; N,
4.62. Found: C, 55.61; H, 5.31; N, 4.59.
1
(d), 120.1 (q, J CF ) 277.1 Hz), 125.3 (d), 125.1 (d), 127.8 (d),
2
127.9 (d), 130.9 (s), 147.0 (q, J CF ) 30.6 Hz), 151.3 (s), 158.2
(s), 168.7 (s); 19F NMR (235 MHz, CDCl3) δ -63.9 (s, 3F), -72.7
(s, 3F); HRMS calcd for C27H32F3NO3 475.2334, found 475.2342.
Anal. Calcd for C27H32F3NO3: C, 68.21; H, 6.73; N, 2.94.
Found: C, 68.30; H, 6.70; N, 2.92.
Isop r op yl 4-Ch lor o-4,4-d iflu or o-3-(4-m eth oxya n ilin o)-
2-bu t en oa t e (4c). Flash chromatography [n-hexane/EtOAc
(12:1)] on silica gel gave a yellow solid (64%): mp 60-62 °C;
1H NMR (250 MHz, CDCl3) δ ((Z)-enamino tautomer) 1.21 (d,
J ) 6.2 Hz, 6H), 3.73 (s, 3H), 5.00 (m, 1H), 5.17 (s, 1H), 6.72-
7.19 (m, 4H), 9.64 (brs, 1H); (imino tautomer) 1.17 (d, J ) 6.2
Hz, 6H), 3.42 (s, 2H), 3.72 (s, 3H), 4.95 (m, 1H), 6.62-7.19
(m, 4H); 13C NMR (62.8 MHz, CDCl3) δ ((Z)-enamino tautomer)
(+)-(2S,5S,1R)-2-(1-(4-Iod op h en yl)-1-m et h ylet h yl)-5-
m eth ylcycloh exyl (Z)-4,4,4-Tr iflu or o-3-(4-m eth oxyan ilin o)-
2-bu ten oa te (4l). Flash chromatography [n-hexane/AcOEt
(30:1)] on silica gel gave a yellow oil (69%): [R]25 +103.4 (c
D
0.96, CHCl3); 1H NMR (250 MHz, CDCl3) δ 0.74-2.07 (m, 17H),
3.69 (s, 3H), 4.49 (s, 1H), 4.70 (dt, J 1 ) 10.6 Hz, J 2 ) 4.1 Hz,
1H), 6.76 (d, J ) 10.0 Hz, 2H), 6.95 (d, J ) 11.1 Hz, 2H), 7.03
(d, J ) 8.8 Hz, 2H), 7.50 (d, J ) 10.9 Hz, 2H), 9.50 (brs, 1H);
13C NMR (62.8 MHz, CDCl3) δ 21.7 (q), 23.8 (d), 26.4 (t), 31.2
(q), 33.8 (t), 39.2 (s), 41.7 (t), 50.6 (d), 55.3 (q), 73.8 (d), 87.5
3
22.7 (q), 56.1 (q), 68.0 (d), 87.2 (q, J CF ) 6.0 Hz), 114.5 (d),
122.8 (q, 1J CF ) 243.4 Hz), 129.9 (d), 131.5 (s), 152.9 (q, 2J CF
)
21.3 Hz), 159.2 (s), 170.2 (s); (imino tautomer) 22.3 (q), 35.2
(t), 56.1 (q), 70.5 (d), 114.7 (d), 121.4 (d), 122.3 (q, 1J CF ) 231.2
2
Hz), 139.1 (s), 155.5 (q, J CF ) 20.8 Hz), 158.6 (s), 166.9 (s);
19F NMR (235 MHz, CDCl3) δ ((Z)-enamino tautomer) -52.0
3
1
(q, J CF ) 5.2 Hz), 90.5 (s), 113.9 (d), 120.0 (q, J CF ) 277.2
(s, 2F); (imino tautomer) -59.9 (s, 2F); HRMS calcd for C14H16
-
Hz), 127.4 (s), 127.6 (d), 128.0 (d), 130.8 (s), 136.8 (d), 147.3
2
(q, J CF ) 30.7 Hz), 151.3 (s), 158.2 (s), 168.6 (s); 19F NMR
ClF2NO3 319.0786, found 319.0789.
(235 MHz, CDCl3) δ -33.7 (s, 3F), -72.7 (s, 3F); HRMS calcd
3-[(Z)-2-Ch lor o-2,2-d iflu or o-1-(4-m et h oxya n ilin o)et h -
yled en e]tetr a h yd r o-2-fu r a n on e (4d ). Flash chromatogra-
phy [n-hexane/EtOAc (3:1)] on silica gel gave a yellow solid
for C27H31F3NO3I 601.1300, found 601.1303.
(+)-(2S,5S,1R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)-cy-
cloh exyl(Z)-4-ch lor o-4,4-d iflu or o-3-(4-m et h oxya n ilin o)-
2-bu ten oa te (4m ). Flash chromatography [n-hexane/AcOEt
1
(82%): mp 59-61 °C; H NMR (250 MHz, CDCl3) δ 3.07 (m,
2H), 3.73 (s, 3H), 4.34 (t, J ) 7.4 Hz, 2H), 6.70 (d, J ) 8.9 Hz,
2H), 7.00 (d, J ) 8.7 Hz, 2H), 9.40 (brs, 1H); 13C NMR (62.8
(30:1)] on silica gel gave a yellow oil (70%): [R]25 +29.9 (c
D
4
1
MHz, CDCl3) δ 26.5 (t, J CF ) 4.7 Hz), 55.3 (q), 66.0 (t), 94.7
1.06, CHCl3); H NMR (250 MHz, CDCl3) δ 0.89 (d, J ) 6.2
1
(s), 113.9 (d), 122.4 (t, J CF ) 296.4 Hz), 127.5 (d), 131.9 (s),
Hz, 3H), 1.27 (s, 3H), 1.61 (s, 3H), 0.91-2.06 (m, 8H), 2.75 (d,
J ) 16.3 Hz, 1H), 2.83 (d, J ) 16.7 Hz, 1H), 3.82 (s, 3H), 4.57
(s, 3H), 4.82 (td, J 1 ) 10.3 Hz, J 2 ) 4.1 Hz, 1H), 6.85 (d, J )
8.8 Hz, 2H), 7.17 (d, J ) 8.2 Hz, 2H), 7.29-7.31 (m, 5H), 9.58
(brs, 1H); 13C NMR (62.8 MHz, CDCl3) δ ((Z)-enamino tau-
tomer) 21.7 (q), 25.5 (d), 26.5 (t), 27.5 (d), 31.1 (q), 35.5 (t),
2
147.5 (t, J CF ) 26.2 Hz), 158.0 (s), 174.5 (s); 19F NMR (235
MHz, CDCl3) δ -50.2 (s, 2F); HRMS calcd for C13H12F2NO3Cl
303.0477, found 303.0473. Anal. Calcd for C13H12F2NO3Cl: C,
51.40; H, 3.95; N, 4.61. Found: C, 51.45; H, 3.88; N, 4.60.
Isop r op yl 4,4,5,5,5-P en ta flu or o-3-(4-m eth oxya n ilin o)-
2-p en ten oa te (4e). Flash chromatography [n-hexane/EtOAc
(10:1)] on silica gel gave a yellow oil (100%): 1H NMR (250
MHz, CDCl3) δ ((Z)-enamino tautomer) 1.20 (d, J ) 6.3 Hz,
6H), 3.71 (s, 3H), 4.91-5.03 (m, 1H), 5.20 (s, 1H), 6.70-7.01
(m, 4H), 9.49 (brs, 1H); (imino tautomer) 1.17 (d, J ) 6.2 Hz,
6H), 3.39 (s, 2H), 3.73 (s, 3H), 4.91-5.03 (m, 1H), 6.70-7.01
(m, 4H); 13C NMR (62.8 MHz, CDCl3) δ ((Z)-enamino tautomer)
3
39.6 (s), 41.8 (t), 50.6 (d), 55.3 (q), 73.9 (d), 86.9 (q, J CF ) 7.0
1
Hz), 113.6 (d), 114.2 (d), 118.0 (q, J CF ) 291.8 Hz), 125.3 (d),
2
127.8 (d), 127.9 (d), 130.8 (s), 151.3 (s), 151.4 (q, J CF ) 25.1
Hz), 158.2 (s), 168.8 (s); (imino tautomer) 21.7 (q), 23.0 (d),
26.1 (t), 29.1 (d), 31.3 (q), 33.6 (t), 34.3 (t), 39.6 (s), 41.1 (t),
1
50.0 (d), 55.3 (q), 75.7 (d), 118.0 (q, J CF ) 291.8 Hz), 120.4
(d), 123.1 (d), 125.0 (d), 125.1 (d), 128.9 (d), 139.9 (s), 151.6
2
(s), 155.4 (q, J CF ) 27.9 Hz), 157.6 (s), 166.3 (s); 19F NMR
3
21.8 (q), 55.2 (q), 67.5 (d), 92.6 (q, J CF ) 7.0 Hz), 111.2 (tq,
2
1
1J CF ) 264.0 Hz, J CF ) 38.8 Hz), 118.7 (qt, J CF ) 281.6 Hz,
(235 MHz, CDCl3) δ ((Z)-enamino tautomer) -51.5 (d, J )
167.8 Hz, 1F), -52.4 (d, J ) 167.8 Hz, 1F); (imino tautomer)
-60.4 (s, 2F); HRMS calcd for C27H32F2NO3Cl 491.2038, found
491.2040. Anal. Calcd for C27H32F2NO3Cl: C, 65.98; H, 6.51;
N, 2.85. Found: C, 65.95; H, 6.62; N, 2.92.
2J CF ) 37.1 Hz), 113.7 (d), 127.8 (d), 131.8 (s), 146.3 (q, 2J CF
26.8 Hz), 158.1 (s), 168.6 (s); (imino tautomer) 21.4 (q), 34.9
)
1
2
(t), 55.3 (q), 69.7 (d), 111.2 (tq, J CF ) 264.0 Hz, J CF ) 38.8
1
2
Hz), 114.3 (d), 118.7 (qt, J CF ) 281.6 Hz, J CF ) 37.1 Hz),
2
120.7 (d), 139.9 (s), 153.4 (q, J CF ) 26.8 Hz), 157.9 (s), 166.0
Meth yl (Z)-4,4,4-Tr iflu or o-3-(4-m eth oxyan ilin o)-2-m eth -
yl-2-bu ten oa te (4o). Flash chromatography [n-hexane/EtOAc
(15:1)] on silica gel gave a yellow oil (92%): 1H NMR (250 MHz,
(s); 19F NMR (235 MHz, CDCl3) δ ((Z)-enamino tautomer)
-83.3 (s, 3F), -112.0 (s, 2F); (imino tautomer) -81.7 (s, 3F),
-117.0 (s, 2F); HRMS calcd for C15H16F5NO3 353.1050, found
353.1059.
5
CDCl3) δ ((Z)-enamino tautomer) 1.91 (q, J HF ) 1.2 Hz, 3H),
3.63 (s, 3H), 3.58 (s, 3H), 6.71 (d, J ) 8.9 Hz, 2H), 6.79 (d, J
) 8.9 Hz, 2H), 9.32 (brs, 1H); (imino tautomer) 1.30 (d, J )
7.0 Hz, 3H), 3.63 (s, 3H), 3.68 (s, 3H), 3.78 (q, J ) 7.3 Hz,
1H), 6.60 (d, J ) 8.9 Hz, 2H), 6.79 (d, J ) 8.9 Hz, 2H); 13C
NMR (62.8 MHz, CDCl3) δ ((Z)-enamino tautomer) 12.9 (q),
(+)-Isop r op yl (Z)-4,4,4-Tr iflu or o-3-[(1S)-1-p h en yleth yl-
a m in o]-2-bu ten oa te (4i). Flash chromatography [n-hexane/
EtOAc (10:1)] on silica gel gave a yellow oil (65%): [R]25
D
+366.3 (c 1.08, CHCl3); 1H NMR (250 MHz, CDCl3) δ 1.18 (d,
J ) 6.2 Hz, 3H), 1.19 (d, J ) 6.2 Hz, 3H), 1.46 (d, J ) 6.7 Hz,
3H), 4.62-4.69 (m, 1H), 4.92-5.02 (m, 1H), 5.01 (s, 1H), 7.13-
7.29 (m, 5H), 8.57 (brd, J ) 9.1 Hz, 1H); 13C NMR (62.8 MHz,
3
51.9 (q), 55.3 (q), 88.9 (q, J CF ) 5.7 Hz), 114.1 (d), 120.4 (q,
2
1J CF ) 277.0 Hz), 126.7 (d), 127.8 (s), 135.3 (d), 156.5 (q, J CF
) 24.7 Hz), 169.8 (s); (imino tautomer) 13.2 (q), 39.3 (d), 52.7
J . Org. Chem, Vol. 67, No. 14, 2002 4675

Fustero et al.
1
(q), 55.3 (q), 114.4 (d), 119.9 (q, J CF ) 278.2 Hz), 119.9 (d),
tautomer) 0.65 (d, J ) 7.3 Hz, 3H), 0.78-2.03 (m, 17H), 3.14
(q, J ) 7.3 Hz, 1H), 3.75, (s, 3H), 4.77 (td, J 1 ) 10.7 Hz, J 2 )
139.8 (d), 157.4 (s), 157.6 (q, J CF ) 24,7 Hz), 169.8 (s); 19F
2
NMR (235 MHz, CDCl3) δ ((Z)-enamino tautomer) -58.6 (s,
3F); (imino tautomer) -68.1 (s, 3F); HRMS calcd for C13H14F3-
NO3 289.0925, found 289.0915. Anal. Calcd for C13H14F3NO3:
C, 53.97; H, 4.84; N, 4.84. Found: C, 54.01; H, 4.79; N, 4.80.
4.3 Hz, 1H), 6.74 (d, J ) 8.8 Hz, 2H), 6.92 (d, J ) 8.8 Hz, 2H),
6.85-7.19 (m, 5H); 13C NMR (100 MHz, CDCl3) δ ((Z)-enamino
tautomer) 13.5 (q), 24.9 (q), 26.0 (d), 26.5 (t), 29.5 (q), 31.3 (q),
34.2 (t), 39.6 (s), 39.9 (d), 41.8 (t), 55.4 (q), 74.6 (d), 75.9 (d),
114.2 (d), 120.3 (d), 123.1 (q, 1J CF ) 297.0 Hz), 125.1 (d), 128.0
Eth yl (Z)-4,4,4-Tr iflu or o-3-(4-m eth oxya n ilin o)-2-eth yl-
2-bu ten oa te (4p ). Flash chromatography [n-hexane/EtOAc
(10:1)] on silica gel gave a yellow oil (80%): 1H NMR (250 MHz,
CDCl3) δ ((Z)-enamino tautomer) 0.97 (t, J ) 7.2 Hz, 3H), 1.21
(t, J ) 7.1 Hz, 3H), 2.38 (q, J ) 3.9 Hz, 2H), 3.67 (s, 3H), 4.11
(q, J ) 7.0 Hz, 2H), 6.74 (d, J ) 5.6 Hz, 2H), 6.80 (d, J ) 5.6
Hz, 2H), 9.24 (brs, 1H); (imino tautomer) 0.97 (t, J ) 7.2 Hz,
3H), 1.20 (t, J ) 7.1 Hz, 3H), 1.70 (m, 1H), 1.95 (m, 1H), 3.62
(m, 1H), 3.71 (s, 3H), 4.11 (q, J ) 7.0 Hz, 2H), 6.74 (d, J ) 5.6
Hz, 2H), 6.80 (d, J ) 5.6 Hz, 2H); 13C NMR (62.8 MHz, CDCl3)
δ ((Z)-enamino tautomer) 14.1 (q), 14.5 (q), 20.9 (t), 55.5 (q),
2
(d), 138.1 (s), 151.8 (s), 157.5 (s), 158.2 (q, J CF ) 31.9 Hz),
168.8 (s); (imino tautomer) 12.6 (q), 21.6 (q), 22.6 (d), 26.2 (t),
29.5 (q), 31.2 (q), 34.4 (t), 39.2 (s), 40.5 (d), 41.2 (t), 50.2 (d),
1
55.4 (q), 75.6 (d), 114.4 (d), 119.9 (d), 123.1 (q, J CF ) 297.0
Hz), 124.9 (d), 127.7 (d), 140.4 (s), 151.9 (s), 157.5 (s), 158.2
2
(q, J CF ) 31.9 Hz), 168.7 (s); 19F NMR (235 MHz, CDCl3) δ
((Z)-enamino tautomer) -59.0 (s, 3F); (imino tautomer) -67.9
(s, 3F). HRMS calcd for C28H34F3NO3 489.2490, found 489.2491.
Gen er a l P r oced u r e for th e Syn th esis of â-Tr iflu or o-
m eth yl â-En a m in o Am id es 5. To a stirred solution of LDA
(12.6 mmol) in THF (10 mL) at -60 °C was added dropwise a
solution of the corresponding amide (6.3 mmol) in THF (10
mL), and the resulting mixture was stirred for 2 h. The
temperature of the reaction was brought to -78 °C prior to
the additon of a solution of imidoyl chloride 1a (1.5 g, 6.3
mmol) in THF (15 mL). After the total disappearance of the
starting materials (TLC), the reaction was quenched with
saturated NH4Cl (1 mL) and the solvent was removed under
reduced pressure. The residue was dissolved in dichlo-
romethane and washed with brine. The organics were dried
with MgSO4, filtered, and concentrated to furnish the crude
products. Column chromatography on silica gel (prewashed
with a 2% solution of Et3N in n-hexanes) gave the pure
enamino amides 5.
1
60.8 (t), 77.2 (s), 114.5 (d), 120.0 (q, J CF ) 269.6 Hz), 123.1
2
(d), 135.5 (s), 142.1 (q, J CF ) 30.5 Hz), 157.3 (s), 169.8 (s);
(imino tautomer) 11.7 (q), 13.9 (q), 20.8 (t), 47.0 (d), 55.4 (q),
1
61.7 (t), 114.4 (d), 119.9 (d), 120.0 (q, J CF ) 269.6 Hz), 140.1
2
(s), 156.4 (s), 157.1 (q, J CF ) 31.4 Hz), 168.8 (s); 19F NMR
(235 MHz, CDCl3) δ ((Z)-enamino tautomer) -58.0 (s, 3F);
(imino tautomer) -68.2 (s, 3F); HRMS calcd for C15H18 F3NO3
317.1238, found 317.1237.
Meth yl (Z)-4-Ch lor o-4,4-d iflu or o-3-(4-m eth oxya n ilin o)-
2-m eth yl-2-bu ten oa te (4s). Flash chromatography [n-hex-
ane/EtOAc (8:1)] on silica gel gave a yellow oil (72%): 1H NMR
5
(400 MHz, CDCl3) δ ((Z)-enamino tautomer) 2.01 (q, J HF
)
2.5 Hz, 3H), 3.60 (s, 3H), 3.68 (s, 3H), 6.69 (d, J ) 5.5 Hz,
2H), 6.82 (d, J ) 6.5 Hz, 2H), 8.89 (brs, 1H); (imino tautomer)
1.36 (d, J ) 7.5 Hz, 3H), 3.63 (s, 3H), 3.70 (s, 3H), 3.84 (q, J
) 7.2 Hz, 1H), 6.69 (d, J ) 5.5 Hz, 2H), 6.82 (d, J ) 6.5 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ ((Z)-enamino tautomer) 17.2
(q), 51.8 (q), 52.1 (q), 106.77 (s), 114.5 (d), 119.8 (d), 120.4 (t,
1J CF ) 277.0 Hz), 139.2 (s), 146.7 (t, 2J CF ) 24.1 Hz), 157.3 (s),
169.8 (s); (imino tautomer) 13.8 (q), 39.6 (d), 52.5 (q), 55.3 (q),
(+)-(Z)-[(4S)-4-Ben zyl-2-oxo-1,3-oxa zola n -3-ilo]-4,4,4-
tr iflu or o-3-(4-m eth oxya n ilin o)-2-bu ten -1-on a (5a ). Flash
chromatography [n-hexane/EtOAc (3:1)] on silica gel gave a
1
yellow oil (94%): [R]25 +60.2 (c 1.36, CHCl3); H NMR (250
D
MHz, CDCl3) δ 2.73 (dd, J 1 ) 13.3 Hz, J 2 ) 9.7 Hz, 1H), 3.31
(dd, J 1 ) 13.3 Hz, J 2 ) 3.2 Hz, 1H), 3.75 (s, 3H), 4.08-4.13
(m, 2H), 4.65-4.70 (m, 1H), 6.76-7.30 (m, 10H), 10.68 (brs,
1H); 13C NMR (62.8 MHz, CDCl3) δ 38.0 (t), 55.0 (d), 55.3 (q),
65.7 (t), 85.6 (q, 3J CF ) 5.5 Hz), 113.9 (d), 119.9 (q, 1J CF ) 277.6
Hz), 127.2 (d), 128.0 (d), 128.8 (d), 129.3 (d), 130.0 (s), 135.3
114.0 (d), 119.3 (d), 123.5 (t, 1J CF ) 277.0 Hz), 134.2 (t, 2J CF
)
24.1 Hz), 135.3 (s), 156.4 (s), 169.0 (s); 19F NMR (376 MHz,
CDCl3) δ ((Z)-enamino tautomer) -48.7 (s, 2F); (imino tau-
tomer) -55.7 (d, J FF ) 167.2 Hz, 1F), -56.9 (d, J FF ) 167.2
Hz, 1F); HRMS (FAB) calcd for (M+ + 1) C13H15ClF2NO3
306.0708, found 306.0696.
(s), 149.6 (q, 2J CF ) 30.7 Hz), 153.0 (s), 158.5 (s), 167.2 (s); 19
F
NMR (235 MHz, CDCl3) δ -63.5 (s, 3F); HRMS calcd for
C
21H19F3N2O4 420.1295, found 420.1294.
(-)-(2S,5S,1R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)-cy-
cloh exyl (Z)-4-Ch lor o-4,4-d iflu or o-3-(4-m eth oxya n ilin o)-
2-m eth yl-2-bu ten oate (4u ). Flash chromatography [n-hexane/
(+)-(5S)-(4-Met h oxyb en zyl)-5-(4-m et h oxyb en zyloxy-
m eth yl)-3-[(Z)-2,2,2-tr iflu or o-1-(4-m eth oxyan ilino)etiliden ]-
a zola n -2-on a (5c). Recrystallization [n-hexane/EtOH (50:1)]
EtOAc (30:1)] on silica gel gave a yellow oil (80%): [R]25
D
1
-113.9 (c 0.89, CHCl3); H NMR (300 MHz, CDCl3) δ (imino
gave a white solid (82%): mp 85-86 °C; [R]25 +261.4 (c 1.08,
D
tautomer) 0.66 (d, J ) 7.3 Hz, 3H), 0.81 (d, J ) 6.6 Hz, 3H),
CHCl3); 1H NMR (250 MHz, CDCl3) δ 2.58-2.69 (m, 1H), 2.80-
2.93 (m, 1H), 3,36 (dd, J 1 ) 4.4 Hz, J 2 ) 1.7 Hz, 2H), 3.65 (m,
1H), 3.71 (s, 6H), 3.73 (s, 3H), 4.04 (d, J ) 14.7 Hz, 1H), 4.32
(s, 2H), 4.81 (d, J ) 14.7 Hz, 1H), 6.71-7.17 (m, 12H), 9.42
(brs, 1H); 13C NMR (62.8 MHz, CDCl3) δ 26.8 (t), 44.3 (d), 54.3
(q), 55.1 (q), 55.2 (q), 70.6 (t), 72.6 (t), 108.0 (q, 3J CF ) 1.7 Hz),
113.7 (d), 113.8 (d), 113.9 (d), 121.3 (q, 1J CF ) 288.2 Hz), 124.8
(d), 128.5 (s), 129.3 (d), 129.4 (d), 129.6 (s), 134.8 (s), 137.2 (q,
2J CF ) 31.8 Hz), 156.7 (s), 158.91 (s), 159.2 (s), 170.7 (s); 19F
NMR (235 MHz, CDCl3) δ -61.1 (s, 3F); HRMS calcd for
1.06 (s, 3H), 1.14 (s, 3H), 0.83-1.92 (m, 7H), 1.98 (td, J 1
)
12.0 Hz, J 2 ) 3.5 Hz, 1H), 3.15 (q, J ) 7.3 Hz, 1H), 3.77, (s,
3H), 4.77 (td, J 1 ) 10.7 Hz, J 2 ) 4.5 Hz, 1H), 6.72 (d, J ) 9.0
Hz, 2H), 6.84-6.86 (m, 2H), 6.91 (d, J ) 8.8 Hz, 2H), 7.01-
7.04 (m, 3H); 13C NMR (75 MHz, CDCl3) δ (imino tautomer)
14.3 (q), 22.7 (q), 23.4 (d), 27.2 (t), 30.7 (q), 32.2 (q), 35.4 (t),
39.2 (s), 42.0 (d), 42.2 (t), 51.2 (d), 56.5 (q), 76.5 (d), 115.4 (d),
120.9 (d), 123.3 (t, 1J CF ) 226.7 Hz), 125.9 (d), 126.0 (d), 128.8
2
(d), 140.5 (s), 152.0 (s), 157.4 (s), 161.6 (t, J CF ) 26.2 Hz),
168.8 (s); 19F NMR (282 MHz, CDCl3) δ ((Z)-enamino tautomer)
-48.7 (s, 2F); (imino tautomer) -55.2 (d, J ) 166.7 Hz, 1F),
-56.4 (d, J ) 166.7 Hz, 1F); HRMS calcd for C28H34F2NO3Cl
505.2197, found 505.2195.
C
C
30H31N2O5F3 556.2185, found 556.2185. Anal. Calcd for
30H31F3N2O5: C, 64.69; H, 5.57; N, 5.03. Found: C, 64.72; H,
5.55; N, 4.89.
Gen er a l P r oced u r e for th e Syn th esis of γ-F lu or in a ted
â-Am in o Ester s (6). To a solution of anhydrous zinc iodide
(1.91 g, 6.0 mmol) in dry CH2Cl2 (20 mL) at 0 °C were added
the corresponding â-fluoroalkyl â-amino esters 4 (2.0 mmol).
The resulting mixture was stirred at the same temperature
for 1 h after which 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 was then
quenched with saturated ammonium chloride solution, and the
reaction mixture was extracted with dichloromethane (3 × 20
mL). The organic layers were combined, washed with brine,
(-)-(2S,5S,1R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)-cy-
cloh exyl (Z)-4,4,4-Tr iflu or o-3-(4-m eth oxyan ilin o)-2-m eth yl-
2-bu ten oa te (4v). Flash chromatography [n-hexane/EtOAc
(30:1)] on silica gel gave a yellow oil ((Z)-enamino tautomer)/
solid (imino tautomer) (85%): mp (imino tautomer) 122-123
1
°C; [R]25 -165.5 (c 1.03, CHCl3); H NMR (400 MHz, CDCl3)
D
δ ((Z)-enamino tautomer) 0.79 (d, J ) 6.3 Hz, 3H), 0.82-1.97
(m, 14H), 1.39 (q, 4J FH ) 6.3 Hz, 3H), 3.72, (s, 3H), 4.87 (td, J 1
) 10.7 Hz, J 2 ) 4.3 Hz, 1H), 6.76 (d, J ) 9.2 Hz, 2H), 6.83 (d,
J ) 9.0 Hz, 2H), 7.07-7.19 (m, 5H), 9.29 (brs, 1H); (imino
4676 J . Org. Chem., Vol. 67, No. 14, 2002

Stereoselective Synthesis of Fluorinated â-Amino Acids
and dried over sodium sulfate. After filtration, the solvents
were removed under reduced pressure to provide the crude
reaction mixture consisting of 6 and/or 7. Purification was
carried out as indicated in each example.
(235 MHz, CDCl3) δ -73.8 (d, J ) 7.3 Hz, 3F). HRMS calcd
for C13H16F3NO3 291.1082, found 291.1087.
(()-Eth yl (2R*,3R*)-2-Eth yl-4,4,4-tr iflu or o-3-(4-m eth -
oxya n ilin o)-bu ta n oa te (6g). Flash chromatography [n-hex-
ane/EtOAc (10:1)] on silica gel gave a yellow oil (94%): 1H
NMR (400 MHz, CDCl3) δ 0.85 (t, J ) 5.6 Hz, 3H), 1.16 (t, J
) 5.2 Hz, 3H), 1.65 (m, 1H), 1.75 (m, 1H), 2.52-2.58 (m, 1H),
3.60 (brs, 1H), 3.66 (s, 3H), 4.08 (q, J ) 7.0 Hz, 2H), 4.14 (m,
1H), 6.58 (d, J ) 6.3 Hz, 2H), 6.70 (d, J ) 6.7 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 11.5 (q), 14.0 (q), 21.4 (t), 47.6 (d),
(()-Isop r op yl 4,4,4-Tr iflu or o-3-(4-m eth oxya n ilin o)-bu -
t a n oa t e (6a ). Flash chromatography [n-hexane/EtOAc (10:
1
1)] on silica gel gave a white solid (70%): mp 76-78 °C; H
NMR (250 MHz, CDCl3) δ 1.06 (d, J ) 6.2 Hz, 3H), 1.12 (d, J
) 6.2 Hz, 3H), 2.48 (dd, J 1 ) 15.4 Hz, J 2 ) 9.0 Hz, 1H), 2.70
(dd, J 1 ) 15.4 Hz, J 2 ) 4.4 Hz, 1H), 3.37 (brd, J ) 10.0 Hz,
1H), 3.66 (s, 3H), 4.22-4.32 (m, 1H), 4.87-4.97 (m, 1H), 6.61
(d, J ) 9.1 Hz, 2H), 6.70 (d, J ) 9.0 Hz, 2H); 13C NMR (62.8
2
55.6 (q), 58.4 (q, J CF ) 28.9 Hz), 61.0 (t), 114.8 (d), 115.1 (d),
1
125.7 (q, J CF ) 282.0 Hz), 140.2 (s), 153.1 (s), 172.4 (s); 19F
2
MHz, CDCl3) δ 21.5 (q), 21.6 (q), 35.3 (t), 54.7 (q, J CF ) 29.7
NMR (235 MHz, CDCl3) δ -74.0 (d, J ) 7.0 Hz, 3F); HRMS
Hz), 55.6 (q), 68.9 (d), 114.7 (d), 115.7 (d), 125.6 (q, 1J CF ) 282.9
Hz), 139.7 (s), 153.3 (s), 169.0 (s); 19F NMR (235 MHz, CDCl3)
δ -76.3 (d, J ) 7.1 Hz, 3F); HRMS calcd for C14H18F3NO3
305.1238, found 305.1250. Anal. Calcd for C14H18F3NO3: C,
55.34; H, 5.92; N, 4.50. Found: C, 55.28; H, 5.81; N, 4.43.
calcd for C15H20F3NO3 319.1395, found 319.1399.
(()-Meth yl (2R*,3R*)-4-Ch lor o-4,4-d iflu or o-3-(4-m eth -
oxya n ilin o)-2-m eth yl-bu ta n oa te (6j). Flash chromatogra-
phy [n-hexane/AcOEt (8:1)] on silica gel gave a yellow solid
(98%): mp 43-45 °C; 1H NMR (400 MHz, CDCl3) δ 1.22 (d, J
) 7.0 Hz, 3H), 2.93-3.00 (m, 1H), 3.51 (brd, J ) 11.0 Hz, 1H),
3.57 (s, 3H), 3.66 (s, 3H), 4.41-4.50 (m, 1H), 6.63 (d, J ) 9.0
Hz, 2H), 6.70 (d, J ) 9.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
(+)-(3S)-Isopr opyl 4,4,4-Tr iflu or o-3-(4-m eth oxyan ilin o)-
bu ta n oa te ((S)-6a ). Obtained from 6m R by transesterification
with i-PrOH following the procedure described in the litera-
ture.30 Flash chromatography [n-hexane/EtOAc (10:1)] on silica
2
δ 11.9 (q), 40.5 (d), 55.2 (q), 55.6 (q), 63.5 (t, J CF ) 24.1 Hz),
gel gave a white solid (99%): [R]25 +22.5 (c 1.02, CHCl3); mp
114.7 (d), 115.5 (d), 130.2 (t, 1J CF ) 297.5 Hz), 140.1 (s), 153.2
D
77-78 °C. Spectroscopic data (1H, 13C, 19F NMR) and HRMS
(s), 173.5 (s); 19F NMR (376 MHz, CDCl3) δ -59.6 (dd, J FF
168.4 Hz, J FH ) 9.1 Hz, 1F), -58.0 (dd, J FF ) 163.8 Hz, J FH
)
)
are identical to those of (()-6a .
9.1 Hz, 1F); HRMS calcd for C13H16ClF2NO3 307.0786, found
307.0798. Anal. Calcd for C13H16ClF2NO3: C, 50.73; H, 5.20;
N, 4.55. Found: C, 50.87; H, 5.14; N, 4.67.
(()-Isop r op yl 4,4,5,5,5-P en ta flu or o-3-(4-m eth oxya n ili-
n o)-p en t a n oa t e (6c). Flash chromatography [n-hexane/
EtOAc (10:1)] on silica gel gave a yellow oil (98%): 1H NMR
(250 MHz, CDCl3) δ 1.05 (d, J ) 6.2 Hz, 3H), 1.11 (d, J ) 6.2
Hz, 3H), 2.52 (dd, J 1 ) 15.4 Hz, J 2 ) 8.3 Hz, 1H), 2.75 (dd, J 1
) 15.3 Hz, J 2 ) 4.7 Hz, 1H), 3.50 (brd, J ) 10.8 Hz, 1H), 3.67
(s, 3H), 4.45 (m, 1H), 4.89 (m, 1H), 6.62 (d, J ) 9.0 Hz, 2H),
6.72 (d, J ) 8.9 Hz, 2H); 13C NMR (62.8 MHz, CDCl3) δ 21.5
(2S,5S,1R)-5-Met h yl-2(1-m et h yl-1-p h en ylet h yl)cyclo-
h exyl 4,4,4-Tr iflu or o-3-(4-m eth oxyan ilin o)-bu tan oate (6m ).
Flash chromatography [n-hexane/AcOEt (50:1)] on silica gel
gave a yellow oil (85%). (3S,R*)-6m (m a jor d ia ster eom er ):
[R]25D +18.8 (c 1.03, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.43
(q, J ) 11.1 Hz, 1H), 0.65 (d, J ) 6.6 Hz, 3H), 1.08 (s, 3H),
2
(q), 34.7 (t), 53.1 (q, J CF ) 21.1 Hz), 55.5 (q), 68.9 (d), 114.7
(d), 115.5 (d), 110.0-123.0 (signals of the group C2F5 are
obscured due to their low intensity) 139.2 (s), 154.1 (s), 168.1
(s); 19F NMR (235 MHz, CDCl3) δ -81.6 (s, 3F), -119.5 (dd,
J FF ) 274.2 Hz, J FH ) 7.0 Hz, 1F), -126.9 (dd, J FF ) 274.0
Hz, J FH ) 17.8 Hz, 1F); HRMS calcd for C15H18F5NO3 355.1206,
found 355.1201.
Isop r op yl 4,4,4-Tr iflu or o-3-[(1S)-1-p h en yleth yla m in o]-
bu ta n oa te (6e). Pale yellow oil, obtained as a mixture of
diastereomers that were not separated. Data were taken from
the crude diastereomeric mixture (de 10%): yield 50%; 1H
NMR (250 MHz, CDCl3) δ 1.14 (d, J ) 6.2 Hz, 3H), 1.17-1.21
(d, 3 × 3H), 1.25 (d, J ) 6.2 Hz, 3H), 1.28 (d, J ) 6.2 Hz, 3H),
1.58 (brs, 2 × 1H), 2.21-2.63 (m, 2 × 2H), 3.35 (m, 1H), 3.48
(m, 1H), 3.94-4.03 (m, 2 × 1H), 4.86-5.01 (m, 2 × 1H), 7.15-
7.29 (m, 2 × 5H); 19F NMR (235 MHz, CDCl3) δ -74.4 (d, J )
7.1 Hz, 3F), -75.5 (d, J ) 7.1 Hz, 3F).
1.18 (s, 3H), 0.67-2.01 (m, 7H), 1.83 (dd, J 1 ) 15.8 Hz, J 2
)
10.1 Hz, 1H), 2.01 (dd, J 1 ) 15.6 Hz, J 2 ) 4.1 Hz, 1H), 3.20
(brd, J ) 6.4 Hz, 1H), 3.65 (m, 1H), 3.66 (s, 3H), 4.64 (td, J 1
)10.7 Hz, J 2 ) 4.3 Hz, 1H), 6.47 (d, J ) 9.0 Hz, 2H), 6.68 (d,
J ) 8.8 Hz, 2H), 7.04-7.23 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 20.5 (q), 21.3 (d), 25.0 (t), 28.8 (q), 30.0 (q), 33.3 (t),
2
34.2 (t), 38.2 (s), 39.8 (t), 48.9 (d), 52.9 (q, J CF ) 29.7 Hz),
1
54.6 (q), 74.1 (d), 113.6 (d), 114.2 (d), 124.1 (d), 125.4 (q, J CF
) 281.5 Hz), 126.8 (d), 138.9 (s), 151.1 (s), 152.0 (s), 167.3 (s);
19F NMR (282 MHz, CDCl3) δ -76.6 (d, J FH ) 6.1 Hz, 3F);
HRMS calcd for
C27H34F3NO3 477.2490, found 477.2495.
(3R,R*)-6m (m in or d ia ster eom er ): [R]25 -21.1 (c 0.96,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.65-1.73 (m, 16H), 1.74
(dd, J 1 ) 15.9 Hz, J 2 ) 8.6 Hz, 1H), 1.97 (dd, J 1 ) 15.8 Hz, J 2
) 4.3 Hz, 1H), 3.37 (brd, J ) 6.8 Hz, 1H), 3.46 (td, J 1 ) 9.9
Hz, J 2 ) 3.9 Hz, 1H), 3.66 (s, 3H), 3.99 (s, 1H), 4.72 (td, J 1
)10.7 Hz, J 2 ) 4.3 Hz, 1H), 6.55 (d, J ) 8.8 Hz, 2H), 6.69 (d,
J ) 9.0 Hz, 2H), 7.02-7.20 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 21.6 (q), 23.1 (d), 26.2 (t), 29.2 (q), 31.1 (q), 34.3 (t),
(()-Meth yl 4,4,4-Tr iflu or o-3-(4-m eth oxya n ilin o)-2-m e-
th ylbu ta n oa te (6f): (2R*,3R*)-6f. Flash chromatography
[n-hexane/EtOAc (7:1)] on silica gel gave a yellow solid (90%):
2
1
41.3 (s), 45.3 (t), 50.1 (t), 54.1 (d), 54.7 (q, J CF ) 30.8 Hz),
mp 64-66 °C; H NMR (250 MHz, CDCl3) δ 1.23 (d, J ) 7.1
55.5 (q), 74.0 (d), 114.6 (d), 115.6 (d), 125.0 (d), 125.2 (d), 125.9
Hz, 3H), 2.88 (m, 1H), 3.45 (brd, J ) 11.1 Hz, 1H), 3.58 (s,
3H), 3.67 (s, 3H), 4.31-4.41 (m, 1H), 6.63 (d, J ) 8.8 Hz, 2H),
6.70 (d, J ) 9.0 Hz, 2H); 13C NMR (62.8 MHz, CDCl3) δ 11.5
1
(q, J CF ) 221.4 Hz), 127.4 (d), 139.8 (s), 151.7 (s), 153.2 (s),
169.0 (s); 19F NMR (282 MHz, CDCl3) δ -76.3 (d, J ) 7.1 Hz,
2
3F); HRMS calcd for C27H34F3NO3 477.2490, found 477.2495.
(q), 39.6 (d), 52.2 (q), 55.6 (q), 58.4 (q, J CF ) 28.1 Hz), 114.7
1
(d), 115.8 (d), 122.3 (q, J CF ) 282.5 Hz), 139.9 (s), 153.3 (s),
(2S,5S,1R)-5-Met h yl-2(1-m et h yl-1-p h en ylet h yl)cyclo-
h exyl 4-Ch lor o-4,4-d iflu or o-3-(4-m eth oxya n ilin o)-bu ta n -
oa te (6n ). Flash chromatography [n-hexane/AcOEt (50:1)] on
silica gel gave a colorless oil (80%). (3S,R*)-6n (m a jor
173.2 (s); 19F NMR (235 MHz, CDCl3) δ -73.4 (d, J ) 7.3 Hz,
3F); HRMS calcd for C13H16F3NO3 291.1081, found 291.1079.
Anal. Calcd for C13H16F3NO3: C, 53.61; H, 5.54; N, 4.81.
Found: C, 53.66; H, 5.52; N, 4.80. (2S*,3R*)-6f. Obtained and
purified from the crude mixture in the reduction reaction of
4o with NaBH3CN (entry 8, Table 2). Flash chromatography
[n-hexane/EtOAc (7:1)] on silica gel gave a yellow oil (17%):
1H NMR (250 MHz, CDCl3) δ 1.22 (d, J ) 7.1 Hz, 3H), 2.87-
2.96 (m, 1H), 3.63 (s, 3H), 3.66 (s, 3H), 3.84-3.92 (m, 1H), 4.37
(brd, J ) 9.8 Hz, 1H), 6.59 (d, J ) 9.0 Hz, 2H), 6.72 (d, J ) 9.8
Hz, 2H); 13C NMR (62.8 MHz, CDCl3) δ 14.7 (q), 38.7 (d), 52.1
(q), 55.6 (q), 59.6 (q, 2J CF ) 28.9 Hz), 114.8 (d), 114.9 (d), 125.5
d ia st er eom er ): [R]25 +3.2 (c 1.06, CHCl3); 1H NMR (400
D
MHz, CDCl3) δ 0.49 (q, J ) 11.1 Hz, 1H), 0.74 (d, J ) 6.4 Hz,
3H), 1.28 (s, 3H), 1.92 (s, 3H), 0.75-2.17 (m, 7H), 1.97 (dd, J 1
) 15.6 Hz, J 2 ) 10.5 Hz, 1H), 2.20 (dd, J 1 ) 15.4 Hz, J 2 ) 3.7
Hz, 1H), 3.38 (brd, J ) 6.4 Hz, 1H), 3.76 (s, 3H), 3.86 (m, 1H),
4.74 (td, J 1 )10.7 Hz, J 2 ) 4.3 Hz, 1H), 6.60 (d, J ) 9.0 Hz,
2H), 6.78 (d, J ) 9.0 Hz, 2H), 7.18 (m, 1H), 7.30 (brs, 4H); 13
C
NMR (100 MHz, CDCl3) δ 21.5 (q), 22.4 (d), 26.0 (t), 29.8 (q),
30.9 (q), 34.3 (t), 36.3 (t), 39.2 (s), 40.7 (t), 49.9 (d), 55.5 (q),
1
2
(q, J CF ) 282.5 Hz), 140.5 (s), 152.9 (s), 174.2 (s); 19F NMR
59.0 (q, J CF ) 25.1 Hz), 75.1 (d), 114.5 (d), 115.1 (d), 125.2
J . Org. Chem, Vol. 67, No. 14, 2002 4677

Fustero et al.
1
(d), 126.2 (d), 130.2 (q, J CF ) 297.5 Hz), 139.8 (s), 152.0 (s),
Gen er a l P r oced u r e for th e Syn th esis of γ-F lu or in a ted
γ-Am in o Alcoh ols 7. LiAlH4 (69 mg, 1.8 mmol) was added to
a solution of â-amino ester 6 (177 mg, 0.6 mmol) in THF (12
mL) at -50 °C. The resulting mixture was stirred for 2 h at
room temperature under an argon atmosphere. The reaction
was quenched with saturated ammonium chloride solution. A
similar workup as described in the synthesis of â-fluoroalkyl-
â-amino esters 6 yielded crude 7 as a solid.
153.0 (s), 168.3 (s); 19F NMR (282 MHz, CDCl3) δ -60.1 (dd,
J FF ) 161.6 Hz, J FH ) 7.1 Hz 1F), -60.9 (dd, J FF ) 161.6 Hz,
J FH ) 7.1 Hz 1F); HRMS calcd for C27H34ClF2NO3 493.2195,
found 493.2186.
(2S,5S,1R)-2[1-(4-Iod op h en yl)-1-m eth yleth yl]-5-m eth -
ylcycloh exyl 4,4,4-Tr iflu or o-3-(4-m et h oxya n ilin o)-b u -
t a n oa t e (6o). Flash chromatography [n-hexane/AcOEt (10:
1)] on silica gel gave a yellow solid (75%). (3S,R*)-6o (m a jor
(+)-(2R,3R)-4,4,4-Tr iflu or o-3-(4-m eth oxya n ilin o)-2-m e-
th ylbu ta n -1-ol (7a ). Obtained from (2R,3R,R*)-6q. Flash
chromatography [n-hexane/AcOEt (3:1)] on silica gel followed
by recrystallization [n-hexane/CHCl3 (5:1)] gave a white solid
(65%): mp 120-121 °C; [R]25D +29.4 (c 1.01, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 0.90 (d, J ) 7.0 Hz, 3H), 1.62 (brs, 1H),
2.19 (m, 1H), 3.44 (dd, J 1 ) 15.3 Hz, J 2 ) 10.5 Hz, 1H), 3.51
(dd, J 1 ) 15.5 Hz, J 2 ) 4.9 Hz, 1H), 3.66 (s, 3H), 4.19 (m, 1H),
d ia ster eom er ): mp 38-40 °C; [R]25 +42.3 (c 0.08, CHCl3);
D
1H NMR (250 MHz, CDCl3) δ 0.56 (q, J ) 11.8 Hz, 1H), 0.67
(d, J ) 6.4 Hz, 3H), 1.06 (s, 3H), 1.15 (s, 3H), 0.70-1.84 (m,
7H), 1.90 (dd, J 1 ) 15.7 Hz, J 2 ) 9.1 Hz, 1H), 2.06 (dd, J 1
)
15.7 Hz, J 2 ) 4.3 Hz, 1H), 3.26 (brd, J ) 10.2 Hz, 1H), 3.67 (s,
3H), 4.64 (td, J 1 ) 10.5 Hz, J 2 ) 4.1 Hz, 2H), 6.53 (d, J ) 8.8
Hz, 2H), 6.70 (d, J ) 8.8 Hz, 2H), 6.95 (d, J ) 8.5 Hz, 2H),
7.49 (d, J ) 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.5
(q), 22.8 (d), 26.1 (t), 29.2 (q), 31.0 (q), 34.3 (t), 35.2 (t), 39.3
(s), 40.9 (t), 50.0 (d), 54.2 (q, 2J CF ) 30.0 Hz), 55.6 (q), 75.1 (d),
6.64 (d, J ) 9.2 Hz, 2H), 6.70 (d, J ) 9.2 Hz, 2H); 13C NMR
2
(75 MHz, CDCl3) δ 10.2 (q), 35.0 (d), 55.6 (q), 56.2 (q, J CF
)
1
27.0), 64.5 (t), 114.8 (d), 115.4 (d), 126.6 (q, J CF ) 283.3 Hz),
140.8 (s), 153.0 (s); 19F NMR (282 MHz, CDCl3) δ -72.6 (d, J
) 7.2 Hz, 3F); HRMS calcd for C12H16F3NO2 263.1133, found
263.1121. Anal. Calcd for C12H16F3NO2: C, 54.75; H, 6.13; N,
5.31. Found: C, 54.80; H, 6.16; N, 5.41.
1
90.1 (s), 114.7 (d), 115.4 (d), 127.6 (d), 125.4 (q, J CF ) 281.5
Hz), 136.9 (d), 139.7 (s), 151.7 (s), 153.2 (s), 168.4 (s); 19F NMR
(235 MHz, CDCl3) δ -76.4 (d, J ) 7.0 Hz, 3F); HRMS calcd
for C27H34F3INO3 604.1535, found 604.1487.
(2S,5S,1R)-5-Met h yl-2(1-m et h yl-1-p h en ylet h yl)cyclo-
h exyl 4,4,4-Tr iflu or o-3-(4-m eth oxya n ilin o)-2-m eth ylbu -
ta n oa te (6q). Flash chromatography [n-hexane/AcOEt (50:
1)] on silica gel gave two white solids (83%). (2R,3R,R*)-6q
(-)-(2S,3S)-4,4,4-Tr iflu or o-3-(4-m eth oxya n ilin o)-2-m e-
th ylbu ta n -1-ol (7a ). Obtained from (2S,3S,R*)-6q. Flash
chromatography [n-hexane/AcOEt (3:1)] on silica gel followed
by recrystallization [n-hexane/CHCl3(5:1)] gave a white solid
(m a jor d ia ster eom er ): mp 96-98 °C; [R]25 -30.4 (c 1.17,
D
(62%): mp 119-121 °C; [R]25 -28.7 (c 0.96, CHCl3). Spectro-
CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.74 (d, J ) 6.6 Hz, 3H),
0.76 (d, J ) 7.1 Hz, 3H), 1.10 (s, 3H), 1.21 (s, 3H), 0.78-1.63
(m, 7H), 1.97 (td, J 1 ) 10.7 Hz, J 2 ) 4.8 Hz, 1H), 2.22 (qd, J 1
) 7.1 Hz, J 2 ) 4.3 Hz, 1H), 3.37 (brd, J ) 10.7 Hz, 1H), 3.64
(s, 3H), 4.30-4.38 (m, 1H), 4.74 (td, J 1 ) 10.7 Hz, J 2 ) 4.3
Hz, 1H), 6.66 (d, J ) 9.2 Hz, 2H), 6.68 (d, J ) 9.2 Hz, 2H),
7.04-7.10 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 11.0 (q), 21.6
(q), 24.3 (d), 26.4 (t), 28.2 (q), 31.1 (d), 34.4 (t), 39.2 (s), 41.2
D
scopic data (1H, 13C,19F NMR) and HRMS are identical to those
of (2R,3R)-7a .
Cr ysta l Da ta for (()-7a . Obtained from (2R*,3R*)-6f.
Colorless lath with dimensions 0.73 × 0.20 × 0.08 mm,
orthorhombic, P212121, a ) 5.404(1), b ) 8.133(1), c ) 30.115-
(5) Å, V ) 1323.6(4) Å3, Z ) 4, Dc ) 1.321 g/cm3, F(000) ) 552,
2θmax ) 50°, Mo KR (λ ) 0.71073 Å), ω-scan, T ) 291(2) K,
3302 reflections collected of which 2342 were independent (Rint
) 0.047), direct primary solution and refinement on F2 using
the SHELX97 program,31 173 refined parameters, amino and
OH group hydrogen atoms located in a difference Fourier
synthesis and refined with restrained N-H and O-H bond
lengths, other hydrogen atoms riding, R1[I > 2σ(I)] ) 0.0676,
wR2 (all data) ) 0.1497, residual electron density 0.136
(-0.133) e/Å3, absolute structure could not be determined.
2
(t), 50.0 (d), 55.3 (q), 57.3 (q, J CF ) 27.8 Hz), 75.4 (d), 114.7
1
(d), 115.6 (d), 125.1 (d), 125.2 (d), 125.9 (q, J CF ) 283.2 Hz),
127.9 (d), 140.2 (s), 151.6 (s), 153.1 (s), 172.2 (s); 19F NMR (282
MHz, CDCl3) δ -73.3 (d, J ) 7.2 Hz, 3F); HRMS calcd for
28H36F3NO3 491.2647, found 491.2663. Anal. Calcd for
28H36F3NO3: C, 68.43; H, 7.33; N, 2.85. Found: C, 68.31; H,
C
C
7.21; N, 2.76. (2S,3S,R*)-6q (m in or d ia ster eom er ): mp
110-112 °C; [R]25 +9.4 (c 0.52, CHCl3); H NMR (300 MHz,
1
D
CDCl3) δ 0.25 (q, J ) 12.9 Hz, 1H), 0.59 (d, J ) 6.4 Hz, 3H),
0.98 (d, J ) 7.1 Hz, 3H), 1.08 (s, 3H), 1.18 (s, 3H), 0.96-1.17
(m, 6H), 1.50-1.57 (m, 1H), 1.72-178 (m, 1H), 1.88-1.97 (m,
2H), 3.65 (s, 3H), 4.61 (td, J 1 ) 10.9 Hz, J 2 ) 4.1 Hz, 1H),
6.44 (d, J ) 8.8 Hz, 2H), 6.65 (d, J ) 8.8 Hz, 2H), 7.05-7.23
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 9.5 (q), 21.5 (q), 22.4
(d), 26.1 (t), 29.8 (q), 30.9 (d), 34.4 (t), 38.8 (s), 40.5 (t), 50.1
(()-(2S*,3S*)-4,4,5,5,5-P en taflu or o-3-(4-m eth oxyan ilin o)-
2-m eth yl P en ta n -1-ol (7b). Obtained by reduction of 4t
(entry 23, Table 2). Flash chromatography [n-hexane/AcOEt
(5:1)] on silica gel gave a white solid (20%): mp 70-72 °C; 1H
NMR (300 MHz, CDCl3) δ 0.90 (d, J ) 5.2 Hz, 3H), 1.55 (brs,
1H), 2.27 (m, 1H), 3.37 (dd, J 1 ) 15.4 Hz, J 2 ) 7.9 Hz, 1H),
3.40 (brs, 1H), 3.48 (dd, J 1 ) 15.5 Hz, J 2 ) 3.7 Hz, 1H), 3.67
(s, 3H), 4.40 (m, 1H), 6.62 (d, J ) 6.7 Hz, 2H), 6.70 (d, J ) 6.7
Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 10.2 (q), 35.2 (d), 53.0
(t, 2J CF ) 20.3 Hz), 55.6 (q), 64.3 (t), 114.6 (d), 114.9 (d), 115.0-
125.0 (signals of the group CF2CF3 are obscured due to their
low intensity), 140.8 (s), 152.7 (s); 19F NMR (282 MHz, CDCl3)
2
(d), 55.6 (q), 57.1 (q, J CF ) 28.3 Hz), 75.2 (d), 114.5 (d), 115.4
1
(d), 125.1 (d), 125.5 (q, J CF ) 282.7 Hz), 127.8 (d), 140.0 (s),
152.1 (s), 153.1 (s), 171.3 (s); 19F NMR (282 MHz, CDCl3) δ
-72.5 (d, J ) 7.1 Hz, 3F); HRMS calcd for C28H36F3NO3
491.2647, found 491.2663. Anal. Calcd for C28H36F3NO3: C,
68.43; H, 7.33; N, 2.85. Found: C, 68.41; H, 7.29; N, 2.89.
Cr ysta l Da ta for (2S,3S,R*)-6q: Colorless prism with
dimensions 0.66 × 0.53 × 0.53 mm, orthorhombic, P212121, a
) 8.905(2), b ) 10.655(2), c ) 28.662(6) Å, V ) 2719.5(10) Å3,
Z ) 4, Dc ) 1.201 g/cm3, F(000) ) 1048, 2θmax ) 56°, Mo KR
(λ ) 0.71073 Å), ω-scan, T ) 293(2) K, 7553 reflections
collected of which 6549 were independent (Rint ) 0.024), direct
primary solution and refinement on F2 using the SHELX97
program,31 318 refined parameters, amino group hydrogen
atom located in a difference Fourier synthesis and refined with
restrained N-H bond lengths, other hydrogen atoms riding,
R1[I > 2σ(I)] ) 0.0519, R2 (all data) ) 0.1328, residual electron
density 0.139 (-0.159) e/Å3, absolute structure could not be
determined.
1
2
δ -82.4 (s, 3F), -119.4 (dd, J FF ) 272.8 Hz, J FH ) 8.2 Hz,
1
2
1F), -123.4 (dd, J FF ) 273.0 Hz, J FH ) 21.3 Hz, 1F); HRMS
calcd for C13H16F5NO2 313.1101, found 313.1103. Anal. Calcd
for C13H16F5NO2: C, 49.84; H, 5.11; N, 4.47. Found: C, 49.57;
H, 4.98; N, 4.35.
(-)-(3S)-4,4,4-Tr iflu or o-3-(4-m eth oxya n ilin o)-bu ta n -1-
ol (7c). Obtained from (3S,R*)-6m . Flash chromatography
[n-hexane/AcOEt (1:1)] on silica gel gave a white solid (70%):
1
mp 107-109 °C; [R]25 -53.2 (c 1.03, CHCl3); H NMR (250
D
MHz, CDCl3) δ 1.66 (m, 1H), 2.00 (m, 1H), 3.60 (brs, 1H), 3.68
(s, 3H), 3.78 (m, 2H), 3.90 (m, 1H), 6.72 (d, J ) 8.9 Hz, 2H),
6.72 (d, J ) 9.0 Hz, 2H); 13C NMR (62.8 MHz, CDCl3) δ 31.7
2
(t), 54.9 (q, J CF ) 28.9 Hz), 55.6 (q), 58.8 (t), 114.8 (d), 115.4
1
(d), 126.2 (q, J CF ) 283.4 Hz), 140.4 (s), 153.1 (s); 19F NMR
(235 MHz, CDCl3) δ -76.2 (d, J ) 7.1 Hz, 3F); HRMS calcd
(31) Sheldrick, G.M. SHELXL-97; Unviersity of Go¨ttingen, Go¨ttin-
gen, Germany, 1997.
for C11H14F3NO2 249.0976, found 249.0987.
4678 J . Org. Chem., Vol. 67, No. 14, 2002

Stereoselective Synthesis of Fluorinated â-Amino Acids
Gen er a l P r oced u r e for th e Syn th esis of â-Am in o Acid s
9. A solution of ceric ammonium nitrate (CAN) (2.74 g, 5 mmol)
in water (4 mL) at 0 °C was added to a solution of 6g or 6h
(0.29 g, 1 mmol) in acetonitrile (8 mL). The reaction mixture
was stirred at 0 °C until TLC showed no starting material (2
h). The aqueous phase was extracted with ethyl acetate (5 ×
20 mL). The organic phases were pooled together and washed
in sequence with aqueous solutions of Na2SO3 (20%), NaHCO3
(5%), and brine. The resulting organic layer was then dried
over anhydrous sodium sulfate and concentrated under re-
duced pressure to yield the crude N-unprotected â-amino
esters, which were then used in the next step without further
purification. The crude mixture (ca. 1.0 mmol) was dissolved
in 5 mL of 6 N HCl. The mixture was heated at 50 °C and
stirred for 2 h. The reaction mixture was cooled at room
temperature and extracted with ether (3 × 4 mL). The aqueous
layer was evaporated in vacuo to dryness. Standard Dowex-
50 column chromatography of the residue afforded the free
amino acid 9.
CDCl3) δ -74.0 (d, J ) 7.1 Hz, 3F); HRMS calcd for (M+ + 1)
C6H10F3NO2 186.0741, found 186.0742.
(2S*,3S*)-3-Am in o-4,4,4-tr iflu or o-2-m eth ylbu tan oic Acid
(9b). A Dowex-50 chromatographic column gave a white solid
(50%): mp 155-157 °C; 1H NMR (250 MHz, CDCl3) δ 1.04 (d,
J ) 7.3 Hz, 3H), 2.63 (m, 1H), 4.07 (m, 1H); 13C NMR (62.8
MHz, CDCl3) δ 13.3 (q), 39.7 (d), 54.8 (q, 2J CF ) 30.3 Hz), 124.7
1
(q, J CF ) 280.6 Hz), 180.2 (s); 19F NMR (235 MHz, CDCl3) δ
-70.1 (d, J ) 7.5 Hz, 3F); HRMS calcd for (M+ + 1) C5H8F3-
NO2 172.0585, found 172.0583.
Ack n ow led gm en t. The authors thank Direccio´n
General de Investigacio´n Cient´ıfica y Te´cnica (PPQ
2000-0824) for financial support. B.P. and E.S. also
gratefully acknowledge the Generalitat Valenciana for
predoctoral fellowships.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for the new compounds 4b, 4f-h , 4j, 4n , 4q-r , 4t, 5b,
5d , 6b-c, 6h -i, 6k -l, and 6p and ORTEP diagrams and
crystallographic data for compounds (2S,3S,R*)-6q and
(2R*,3R*)-7a . This material is available free of charge via the
Internet at http://pubs.acs.org.
(2S*,3S*)-3-Am in o-2-eth yl-4,4,4-tr iflu or o-bu ta n oic Acid
(9a ). A Dowex-50 chromatographic column gave a white solid
1
(60%): mp 71-73 °C; H NMR (300 MHz, CDCl3) δ 0.79 (t, J
) 7.3 Hz, 3H), 1.28-1.43 (m, 1H), 1.51-1.62 (m, 1H), 2.37 (dt,
J 1 ) 8.8 Hz, J 2 ) 4.3 Hz, 1H), 3.75-3.86 (m, 1H); 13C NMR
(75 MHz, CDCl3) 11.0 (q), 21.0 (t), 46.8 (d), 54.2 (q, 2J CF ) 30.3
Hz), 123.9 (q, 1J CF ) 280.0 Hz), 178.0 (s); 19F NMR (235 MHz,
J O025621K
J . Org. Chem, Vol. 67, No. 14, 2002 4679