Novel synthesis of α-trifluoromethylated α-amino acid derivatives from γ-hydroxy-α-fluoro-α-trifluoromethyl carboxamides

Article abstract of DOI:10.1021/ol047683y

(Chemical Equation Presented) On treatment with an organoaluminum reagent such as trimethylaluminum or DIBAL-H, γ-hydroxy-α-fluoro-α- trifluoromethyl carboxamides (1) give a single diastereomer of α-amino-α-trifluoromethyl-γ-lactones (2), which are a ring

Full text of DOI:10.1021/ol047683y

ORGANIC
LETTERS
2005
Vol. 7, No. 4
589-592
Novel Synthesis of
-Trifluoromethylated
Derivatives from
-Hydroxy- -fluoro-
Carboxamides
r
r
-Amino Acid
γ
r
r-trifluoromethyl
Kenichi Ogu, Shoji Matsumoto, Motohiro Akazome, and Katsuyuki Ogura*
Department of Applied Chemistry and Biotechnology, Faculty of Engineering,
Chiba UniVersity, 1-33 Yayoicho, Inageku, Chiba 263-8522, Japan
katsuyuki@faculty.chiba-u.jp
Received November 11, 2004
ABSTRACT
On treatment with an organoaluminum reagent such as trimethylaluminum or DIBAL-H,
γ
-hydroxy-
r
-fluoro-r-trifluoromethyl carboxamides (1)
give a single diastereomer of -amino- -trifluoromethyl- -lactones (2), which are a ring-closed form of
r
r
γ
γ
-hydroxy-r-trifluoromethyl-r-amino
acids. This intriguing reaction results from intramolecular replacement of the fluorine atom on the
r-carbon atom with the nitrogen atom of
the amide group, which occurs in an SN2 manner.
Organofluoro compounds have been attracting much attention
in the fields of biochemistry and pharmacology because of
their unique biological properties, which are ascribed to the
so-called mimic effect. This is useful for developing new
drugs.1 Against this background, various methods have been
investigated for synthesizing fluorine-containing R-amino
acids.2 Here, we would like to report a novel synthetic route
leading from γ-hydroxy-R-fluoro-R-trifluoromethyl amides.
To date, we have developed some methods for the
synthesis of organofluoro compounds bearing a perfluoro-
ethylidene [F(CF3)C<] moiety.3 The reaction of various
allylic alcohols with a perfluoropropene-diethylamine adduct
(PPDA) affords R-fluoro-R-trifluoromethyl carboxylic acid
derivatives. These products can be easily converted into
γ-hydroxy-R-fluoro-R-trifluoromethyl carboxamides (1).
To obtain the R-amino-R-trifluoromethyl-γ-lactones, we
examined the substitution of the R-fluorine atom with an
amination reagent. As is known well, the leaving ability of
the fluorine atom is enhanced by metal-fluorine affinity.4
Especially, aluminum exhibits a strong affinity toward the
fluorine atom.5 Posner and co-workers utilized an organoalu-
(2) (a) Lontz, J. F.; Raasch, M. S. (E. I. du Pont de Nemours & Co.).
U.S. Patent 2662915, 1953; Chem. Abstr. 1954, 48, 12795. (b) Christensen,
H, N.; Oxender, D. L. Biochim. Biophys. Acta 1963, 74, 386-391. (c)
Henrick, C. A.; Gracia, B. A. (Zeocon Corp.). Ger. Offen. 2812169, 1978;
Chem. Abstr. 1979, 90, 122072. (d) Soloshonok, V. A.; Yagupol’skii, Y.
L.; Kukhar, V. P. Zh. Org. Khim. 1988, 24, 1638-1644; Chem. Abstr. 1989,
110, 154827. (e) Bravo, P.; Capelli, S.; Meille, S. V.; Viani, F.; Zanda, M.;
Kukhar, V. P.; Soloschonok, V. A. Tetrahedron: Asymmetry 1994, 5, 2009-
2018. (f) Burger, K.; Schierlinger, C.; Hollweck, W.; Mu¨tze, K. Liebigs
Ann. Chem. 1994, 399-406. (g) Burger, K.; Schierlinger, C.; Mu¨tze, K.;
Hollweck, W.; Koksch, B. Liebigs Ann. Chem. 1994, 407-413. (h) Kukhar’,
V. P.; Soloshonok, V. A. Fluorine Containing Amino Acids; John Wiley &
Sons: New York, 1995. (i) Tangco, E. C.; Prakash, G. K. S.; Olah, G. A.
Synlett 1997, 1193-1195.
(1) (a) Welch, J. T.; Eswarakrishnann, S. Fluorine in Bioorganic
Chemistry; John Wiley & Sons: New York, 1990. (b) Resnati, G.
Tetrahedron 1993, 49, 9385-9445. (c) Soloshonok. V. A. Enantiocontrolled
Synthesis of Fluoro-organic Compounds; John Wiley & Sons: New York,
1999. (d) Hiyama, T. Organofluorine Compounds; Springer: Berlin, Tokyo,
2000.
(3) (a) Ogura, K.; Ogu, K.; Ayabe, T.; Sonehara, J.; Akazome, M.
Tetrahedron Lett. 1997, 38, 5173-5176. (b) Ogu, K.; Akazome, M.; Ogura.
K. Tetrahedron Lett. 1998, 39, 305-308. (c) Ogu, K.; Akazome, M.; Ogura,
K. J. Fluorine Chem. 2003, 124, 69-80. (d) Ogu. K.; Akazome, M.; Ogura,
K. J. Fluorine Chem. 2004, 125, 429-438.
10.1021/ol047683y CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/20/2005

minum reagent for C-glycosylation of glycosyl fluorides.6
Alkylaluminum reagents were employed by Maruoka et al.
for the selective alkylation of fluorinated epoxides and
carbonyl compounds.7 Organoaluminum reagents also serve
as catalysts in the nucleophilic substitution of tertiary alkyl
fluorides.8 On the basis of these facts, we examined the
reaction of 2-fluoro-2-trifluoromethyl-3-tosylmethyl-4-pen-
tanolide (3l) with dimethyaluminum anilide. To our great
delight, the expected 2-phenylamino-2-trifluoromethyl-4-
pentanolide (2a) was formed (Scheme 1). However, it was
N-Benzyl-4-hydroxy-2-fluoro-3-tosylmethyl-2-(trifluoro-
methyl)pentanamide (1b) was treated with various organo-
metallic compounds (2.0-2.2 molar equiv), and it was found
that n-butyllithium, triethylborane, n-butyltitanium triiso-
propoxide, diethylzinc and ethylmagnesium bromide did not
give 2b at all. In contrast, some organoaluminum reagents
effectively formed 2b from 1b. On treatment with aluminum
trialkoxide such as Al(OPh)3 and Al(Oi-Pr)3 in refluxing
THF, 3l was formed together with the unchanged 1b. Among
the alkylaluminum reagents examined herein, trimethyl-
aluminum and diisobutylaluminum hydride (DIBAL-H) were
the most effective at giving 2b, affording the latter in 68%
and 77% yields, respectively. It is worth noting that the
product (2b) was formed as a single diastereomer.
Scheme 1. Formation of 2a from 3l Subjected to Reaction
with Dimethylaluminum Anilide
From these preliminary experiments, we selected two
aluminum reagents, trimethylaluminum and DIBAL-H, and
they were subjected to the reaction with N-phenyl-4-hydroxy-
2-fluoro-3-tosylmethyl-2-(trifluoromethyl)pentanamide (1a).
The reaction took place in THF at reflux. After 21 h, the
expected 2-phenylamino-3-tosylmethyl-2-trifluoromethyl-4-
pentanolide (2a) was formed along with a small amount of
the γ-lactone 3l. As shown in Table 1, a high yield in the
found that N-phenyl-3-hydroxy-2-fluoro-3-tosylmethyl-2-
(trifluoromethyl)pentanamide (1a) was mainly formed at the
initial stage, and thence the amount of 2a increased as the
reaction proceeded.9 With these findings, we started to
investigate reacting various γ-hydroxy-R-fluoro-R-trifluoro-
methyl carboxamides (1) with organoaluminum amides.
The starting γ-hydroxy-R-fluoro-R-trifluoromethyl amides
(1) were prepared from R-fluoro-R-trifluoromethyl-γ-lactones
(3) with aniline, benzylamine, or p-anisidine. Detailed
procedures for the preparation of 1 are given in Supporting
Information.
Table 1. Reaction of 1a with Trimethylaluminum or DIBAL-H
yield (%)a
entry
aluminum reagent
Me3Al
equiv
2a
3l
1a
1
2
3
4
5
6
7
none
1.2
2.2
3.2
1.2
2.2
3.2
0
66
69
63
56
78
66
19b
23
14
15
34
7
76b
3
0
0
0
DIBAL-H
0
0
0
a Yields were determined by 1H NMR using Ph3CH as an internal
standard. b Isolated yield.
formation of 2a was attained using more than 1 molar equiv
of the aluminum reagent, though the yield of 2a became
maximal at 2.2 molar equiv of the aluminum reagent.
Interestingly, 2a was also formed as a single diastereomer
in any case. Because its 1H NMR spectrum was very similar
to that of 2b, the structure of 2a was likely to have the same
pentanolide skeleton. Fortunately, this product gave good
quality single crystals. From the ORTEP structure of 2a (see
Supporting Information) obtained by single-crystal X-ray
At first, we examined the types of organometallic reagent
that would be effective for the conversion of 1 to 2.
(4) Bond strength of metal-fluorine: Al-F, 663.6 ( 6.3 kJ/mol; Li-F,
577 ( 21 kJ/mol; Ti-F, 569 ( 34 kJ/mol; Si-F, 552.7 ( 2.1 kJ/mol;
Sn-F, 466.5(13 kJ/mol; Mg-F, 461.9 ( 5.0 kJ/mol. See: Weast, R. C.
Handbook of Chemistry and Physics, 65th ed.; CRC Press: New York,
1984-1985.
(5) (a) Mukaiyama, T.; Murai, Y.; Shoda, S. Chem. Lett. 1981, 431-
432. (b) Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett. 1984,
25, 1379-1382. (c) Kobayashi, S.; Koide, K.; Ohno, M. Tetrahedron Lett.
1990, 31, 2435-2438. (d) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93,
1503-1531.
(7) Ooi, T.; Kagoshima, N.; Maruoka, K. J. Am. Chem. Soc. 1997, 119,
5754-5755.
(8) Ooi, T.; Uraguchi, D.; Kagoshima, N.; Maruoka, K. Tetrahedron Lett.
1997, 38, 5679-5682.
(6) Posner, G. H.; Haines, S. R. Tetrahedron Lett. 1985, 26, 1823-1826.
(9) See Supporting Information
590
Org. Lett., Vol. 7, No. 4, 2005

crystallographic analysis, the R-fluorine atom was replaced
by the phenylamino group with inversion of the configura-
tion.
Table 3. Reaction of 1 with DIBAL-H
Further, the reaction of 1b with trimethylaluminum and
DIBAL-H was studied in detail. The results using various
amounts of the aluminum reagent are given in Table 2. With
yield (%)a
entry
1
R1
R2
R3
Ph
Bn
PMP
Bn
PMP
Bn
PMP
Bn
2
3
1
Table 2. Reaction of 1b with Trimethylaluminum or DIBAL-H
1
2
3
4
5
6
7c
8b
9c
10d
1a
1b
1c
1d
1e
1f
1g
1h
1i
Me
CH2Ts
85
78
80
64
70
79
84
60
46
56
31
7
0
0
0
0
0
0
0
0
0
0
0
10
0
0
0
4
16
5
H
CH2Ts
Me
Me
H
yield (%)a
Me
i-Bu
n-Bu
entry
aluminum reagent
Me3Al
equiv
2b
3l
7b
16
12
0
31
7
3
1b
1j
1
2
3
4
5
6
7c
none
1.2
2.2
3.2
1.2
2.2
3.2
0
10
68
35
15
78
27
90b
72
17
0
45
0
a Isolated yield. b Reaction time: 25 h. c Reaction time: 48 h. d Reaction
time: 50 h.
DIBAL-H
refluxing THF, we obtained a lactol (7) in 20% yield instead
of the corresponding R-benzylamino-γ-lactone (2b) (Scheme
2).
0
a Yields were determined by 1H NMR using Ph3CH as an internal
standard. b Isolated yield. c A lactol (5b) was formed as a byproduct in 30%
yield.
Scheme 2. Reaction of 6 with DIBAL-H
1.2 molar equiv of trimethylaluminum and DIBAL-H, the
yield of 2b was low (10% and 15%, respectively; entries 2
and 5 in Table 2). The use of an excess amount (3.2 molar
equiv) of the aluminum reagent brought about further
reduction of 2b to give a lactol (5b) (entry 7 in Table 2).
The optimal amount of aluminum reagent used was shown
to be 2.2 molar equiv (entries 3 and 6 in Table 2).
In addition, N-benzyl-2-fluoro-2-(trifluoromethyl)octana-
mide (8) remained unchanged under the same reaction
conditions (Scheme 3). Therefore, it is evident that the
present reaction of 1 needs the γ-hydroxy group.
Under these optimal conditions, various 4-hydroxy-2-
fluoro-2-(trifluoromethyl)carboxamides (1) were converted
to R-amino-R-trifluoromethyl-γ-lactones (2). The results are
summarized in Table 3. Although aromatic and aliphatic
amines could be utilized as the amino group (R3NH), the
p-methoxyphenylamino group afforded the best results. This
seems to imply that the electron-donating group accelerates
the migration of the amino group. Furthermore, it was found
that the substituent at the â-position of 1 plays an important
role in the formation of 2. In the absence of the â-substituent
(entries 8-10 in Table 3), the reaction became slower, giving
2 in moderate yield.
Scheme 3. Reaction of 8 with DIBAL-H
As mentioned above, the present reaction gave one
diastereomer of 2. Here, we synthesized an optically active
(2R,3S,4S)-1b according to the synthetic route in Scheme 4.
In the reaction of the optically active 1b with 2.2 equiv of
DIBAL-H in refluxing THF, (2S,3S,4S)-2b was obtained in
76% yield (> 99%ee). The enantiomeric excess of the
product was analyzed by HPLC equipped with a chiral
column to be more than 99%. Thus, it was shown that the
chiral centers of 1 do not undergo any epimerization during
the reaction.
Furthermore, we performed some experiments to gain
insight into the mechanism for the conversion of 1 to 2. First,
we checked whether the γ-hydroxy group is crucial in the
conversion of 1 to 2. When N-benzyl-2-fluoro-4-methoxy-
3-tosylmethyl-2-(trifluoromethyl)pentanamide (6) was sub-
jected to the reaction with 2.2 molar equiv of DIBAL-H in
Org. Lett., Vol. 7, No. 4, 2005
591

Scheme 4. Synthesis of Optically Active 2
Scheme 5. Plausible Mechanism for Formation of 2 from 1
Subjected to Reaction with Alkylaluminum Reagent
From the above results, we propose a plausible mechanism
for forming 2 from 1 (Scheme 5). The starting material (1)
has two reactive sites, a γ-hydroxy group and an amido
group, for the reaction with trimethylaluminum or DIBAL-
H. With 2 molar equiv of the aluminum reagent, it is
reasonably assumed that a dialumino intermediate (B) is
formed. If B cyclizes intramolecularly by the attack of the
resulting aluminum alkoxide on the amide carbonyl group,
a cyclic N-ortho ester (C) would be formed. The subsequent
intramolecular substitution of the R-fluorine atom for the
amide nitrogen leads to an aziridine derivative (D), which
can be transformed to the final product (2) via a ring-opened
intermediate E followed by hydrolysis (workup process). An
analogous reaction to the ring opening of D to form E was
reported by Fioravanti et al.;10 the reaction of an enol ether
of cyclohexanone with an (ethoxycarbonyl)nitrene affords
the corresponding aziridine derivative, which is led to
2-amino-cyclohexan-1-one by the subsequent hydrolysis. It
is likely that, with 1 molar equiv of the aluminum reagent,
1 forms a monoalumino intermediate (A) predominantly. The
intermediate A cyclizes intramolecularly to form an N-ortho
ester (C′) that gives R-fluoro-R-trifluoromethyl-γ-lactone (3)
by hydrolysis (workup). This is the case when R3 is a phenyl
group. Since the amino proton of C′ (R3 ) phenyl) is more
acidic than that of C′ (R3 ) benzyl), it is reasonably supposed
that the intermediate (D′; R3 ) phenyl) can be transformed
to an N-alumino intermediate (C′′; R3 ) phenyl) that
undergoes intramolecular cyclization to give another aziridine
derivative (D′). This path can explain why 1 molar equiv of
the aluminum reagent can transform 1a into 2a in a
reasonable yield.
Thus, we have found a novel synthetic route to R-triflu-
oromethyl-R-aminolactones (2), synthetic equivalents of
γ-hydroxy-R-trifluoromethyl-R-amino acids, by the reaction
of γ-hydroxy-R-fluoro-R-trifluoromethyl carboxamides (1)
with organoaluminum reagents, especially DIBAL-H. This
method is most intriguing in the following aspects. First is
the intramolecular migration of the amine part of 1 from the
amide group to the R-position to substitute the R-fluorine
atom in an SN2 manner. Second, the reaction path is so
stereospecific that only one diastereomer of 2 is formed. We
are now investigating the application of present reaction for
developing a new type of biologically active compounds.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data (NMR, IR, MS), analytical data
of all new synthetic compounds, X-ray crystallographic data
of 2a, and specific rotations of optically active compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Fioravanti, S.; Loreto, M. A.; Pellacani, L.; Tardella, P. A.
Tetrahedron 1991, 47, 5877-5882.
OL047683Y
592
Org. Lett., Vol. 7, No. 4, 2005