Desymmetrization-like catalytic enantioselective fluorination of malonates and its application to pharmaceutically attractive molecules

Article abstract of DOI:10.1002/anie.200704093

(Chemical Equation Presented) At the leading edge: Chiral fluoromalonates can be prepared with very high stereocontrol by enantioselective fluorination of racemic malonates and using a Zn(OAc)₂/DBFOX-Ph catalyst (see scheme), thus providing an

Full text of DOI:10.1002/anie.200704093

Communications
DOI: 10.1002/anie.200704093
Asymmetric Synthesis
Desymmetrization-like Catalytic Enantioselective Fluorination of
Malonates and Its Application to Pharmaceutically Attractive
Molecules**
Dhande Sudhakar Reddy, Norio Shibata,* Jun Nagai, Shuichi Nakamura, Takeshi Toru,* and
Shuji Kanemasa
Optically active organofluorine compounds are attractive in
both modern pharmaceutical chemistry and materials sci-
ence,[1] especially the simple chiral vicinal fluorohydrins that
are employed as important building blocks in the synthesis of
polyfunctional bioactive molecules.[2] Fluorinated malonates
with a fluorine atom at a quaternary carbon center are a class
of versatile and important monofluorinated chiral synthons[2]
utilized in the synthesis of liquid crystals,[3] antitumor agents,[4]
enzyme inhibitors,[5] antiviral agents,[6a] antibiotics,[6b] and
anti-Alzheimer agents.[6c] A variety of enantioselective syn-
theses of fluorinated compounds have been developed for the
elaboration of optically active fluorinated malonates, as well
as their synthetic equivalents such as vicinal fluorohydrins
and fluorinated half hydroxy esters.[2] These approaches
include the enzymatic desymmetrization of substituted
2-fluoromalonic diesters, 2-fluoropropane-1,3-diols, and 2-
fluoro-1,3-diacetoxypropane derivatives, which lead in each
case to similar 2-fluorinated synthons (Scheme 1).[2,7] These
microbial transformations are more practical than the chem-
ical approaches[8] for obtaining the target compounds;
unfortunately, the resulting enantioselectivity is highly
dependent on the substrate and thus significantly limits the
applicability of this process.
We have recently reported a highly enantioselective
fluorination[9] of b-keto esters and oxindoles catalyzed by
À
À
Box Ph/Cu(OTf)2 or DBFOX Ph/Ni(ClO4)2 (Box = bisoxa-
zoline, Tf = triflate, DBFOX = 4,6-dibenzofurandiyl-2,2’-
bisoxazoline.[9a,b] In response to the limitations associated
with the use of microbial desymmetrization for the prepara-
tion of chiral fluorinated malonates and hydroxy esters, we
have now extended our protocol to the desymmetrization-like
enantioselective fluorination of malonates 1 and herein show
À
that a DBFOX Ph/Zn(OAc)2 complex is an effective catalyst
to give the optically active 2-fluorinated malonates 2 with
very high enantioselectivity (up to 99% ee). The 2-fluoro-
malonates 2 can be selectively converted into 2-fluorinated
hydroxy esters 3. The synthetic utility of the method was
demonstrated by the syntheses of pharmaceutically attractive
compounds, namely, chiral fluorinated a-benzyl-b-alanine 4,
fluorinated b-lactam 5, and fluoro-alacepril (6); Scheme 2.
The synthesis of an HIV-1 protease inhibitor was also
achieved through the chemoselective ester–amide exchange
reaction of chiral malonates 2.
Diastereoselective fluorination of malonates has been
reported by Fukumoto and co-workers.[8b–d] l-Menthylphenyl
esters of malonates were fluorinated with fluoropyridinium
triflate in high yield with moderate diastereoselectivities by
Scheme 1. Enzymatic desymmetrization approach for the synthesis of
simple fluorinated synthons.
[*] D. S. Reddy, Prof. N. Shibata, J. Nagai, Dr. S. Nakamura, Prof. T. Toru
Department of Applied Chemistry
Graduate School of Engineering
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
Fax: (+81)52-735-5442
E-mail: nozshiba@nitech.ac.jp
toru@nitech.ac.jp
Prof. S. Kanemasa
Institute for Materials Chemistry and Engineering
Kyushu University, 6–1 Kasugakoen
Kasuga 816-8580 (Japan)
[**] Financial support was provided by KAKENHI (19390029), by a
grant-in-aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the Ministry
of Education, Culture, Sports, Science, and Technology Japan
(19020024).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Desymmetrization-like approach for the synthesis of 2 and
its application to pharmaceutically attractive molecules.
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Angew. Chem. Int. Ed. 2008, 47, 164 –168

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Chemie
using lithium hexamethyldisilazane (LiHMDS). Kaneko and
co-workers also reported that fluorination of chiral
5-substituted 1,3-oxazine-4,6-dione derivatives proceeded
diastereoselectively to give the 5-fluorooxazinediones, which
were readily transformed to optically pure fluoromalonic
acids.[8e] Sodeoka and co-workers reported the enantioselctive
fluorination of lactones and lactams, which were catalyzed by
chiral palladium(II)–bisphosphine complexes.[10] However,
there are no reports of the enantioselective fluorination of
malonates.[9–12] In contrast to b-keto esters, malonates are
nearly symmetrical and less acidic. Therefore, improvement
of the reactivity and discrimination of the two ester moieties
are necessary to achieve high enantiocontrol.
ditions for our desymmetrization-like enantioselective fluo-
rination reaction of malonates (Table 1, entry 7; 90% yield
and 98% ee). Dichloromethane was determined to be a
suitable solvent after screening the reaction with several
different solvents (Table 1, entries 8–10), and molecular
sieves (4 Š) were indispensable for achieving high enantio-
control (Table 1, entry 11).
With the conditions now optimized, the scope of the
desymmetrization-like fluorination reaction was investigated
in terms of the range of substrates that could be tolerated
À
(Table 2). The Zn(OAc)2/DBFOX Ph combination is
Table 2: Desymmetrization-like catalytic enantioselective fluorination of
racemic malonates 1a–i.[a]
We first attempted the fluorination of racemic 2-benzyl-
tert-butyl methyl malonate (1a) with N-fluorobenzene-
sulfonimide (NFSI) under the reported conditions for enan-
tioselective fluorination of b-keto esters, namely, in the
presence of Ni(ClO4)2·6H2O in CH2Cl2 (Table 1).[9a] The
Entry
1
R
t [h][b]
Yield [%][b,c]
ee [%][b,d]
Table 1: Desymmetrization-like catalytic enantioselective fluorination of
racemic malonate 1a: optimization of reaction conditions.[a]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
CH2Ph
Et
Me
Bu36 (62)
Ph
OPh
SPh
NPht
NPht(4-Br)
15 (48)
24 (32)
24 (36)
93 (69)
24 (48)
15 (48)
24
90 (97)
94 (76)
90 (81)
99 (94)
95 (96)
85 (52)
81
98 (89)
96 (94)
99 (95)
99 (93)
98 (91)
90
93
97
Entry
Lewis acid
Solvent
t [h]
Yield [%][b]
ee [%][c]
18
24
91
93
1
2
3
4
5
6
7
8
Ni(ClO4)2·6H2O
Ni(OAc)2·4H2O
Mg(ClO4)2
Mg(OTf)2
Zn(SbF6)2
Zn(OTf)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
Et2O
48
48
48
48
36
36
15
24
62
62
90
97
90
62
59
59
94
90
71
52
49
47
89
86
7
[a] The reaction of 1 with NFSI was carried out in the presence of
Zn(OAc)2 (10 mol%), (R,R)-DBFOX Ph (11 mol%), and M.S. (4 Š) in
À
0
CH2Cl2 under reflux unless otherwise indicated. The absolute config-
uration of 2c was determined by comparing the optical rotation of the
alcohol derivative of 2c with that of the known (S)-ethyl 2-fluoro-3-
hydroxy-2-methylpropanoate, and the stereochemistry of the other
malonates 2 were tentatively assumed to be the same by analogy (see,
the Supporting Information for details). [b] The data given in paren-
theses are the results using Ni(ClO4)2·6H2O instead of Zn(OAc)2 for the
reaction. [c] Yields of isolated products. [d] Determined by HPLC on a
chiral stationary phase or by GC analysis. NPht=N-phthaloyl, NPht(4-
Br)=N-4-bromophtaloyl.
69
87
98
96
68
86
59
9
10
EtOH
CH2Cl2
11[d]
Zn(OAc)2
[a] The reaction of 1a with NFSI was carried out in the presence of Lewis
À
acid (10 mol%), (R,R)-DBFOX Ph (11 mol%), and M.S. (4 Š) in solvent
under reflux. The absolute stereochemistry of 2a was assigned to be S by
derivatization, see Scheme 7 for details. [b] Yields of isolated products.
[c] Determined by HPLC on a chiral stationary phase. [d] The reaction
was carried out in the absence of MS (4 Š). M.S.=molecular sieves.
extremely general for the enantioselective fluorination of a
broad range of malonates 1a–i and is compatible with a wide
range of functional groups such as alkyl, aryl, oxygen, sulfur,
and amino substitutions. The desired products (S)-2a–i were
obtained in high yields, with excellent enantioselectivities of
up to 99% ee (Table 2, entries 1–9). Significantly, the best
conditions reported for the fluorination of b-keto esters,
(S)-2-fluoro-2-benzyl-tert-butyl methyl malonate (2a) was
obtained in excellent yield and high enantioselectivity
(Table 1, entry 1; 97% yield and 89% ee). The conditions
namely, Ni(ClO4)2/DBFOX Ph,[9a] produced fluorinated mal-
À
described for the enantioselective fluorination of oxindoles
[9a]
(Ni(OAc)2·4H2O in CH2Cl2
)
also gave good results
onates with lower enantioselectivities of about 90% ee
(Table 2, entries 1–6; the results are given in parentheses).
To our knowledge, this is the first example of the enantio-
selective fluorination[9–12] of malonates 1 to provide chiral
2-fluorinated malonates 2 and this sequence surely serves as a
potential non-enzymatic strategy for the desymmetrization of
malonates. The stereochemistry of the resulting fluoromalo-
nates 2, can easily be explained by the directional approach of
the fluorinating agent (NSFI) from the less hindered Si face of
the complex formed between the substrates, a ZnII ion, and
(Table 1, entry 2; 90% yield and 86% ee). These enantio-
selectivities are acceptable, but not excellent when compared
with the enantioselective fluorination of b-keto esters and
oxindoles. Optimization experiments for both the Lewis acid
and the solvent were carried out to improve the enantio-
selectivity of the transformation (Table 1, entries 3–7). Zn-
(OAc)2 was found to be very effective for the desymmetriza-
tion-like enantioselective fluorination of malonates. Thus, the
À
use of NFSI, DBFOX Ph (11 mol%), and Zn(OAc)2
À
(10 mol%) in CH2Cl2 at reflux became the standard con-
DBFOX Ph (Scheme 3). This was explained previously for
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165

Communications
Scheme 5. Reagents and conditions: a) LiAl(OtBu)3H (5.0 equiv), THF,
À788C to RT, 1 h, 80%; b) p-TsCl (1.2 equiv), pyridine, CHCl3, 08C to
RT, 12 h, 85%; c) BnNH2 (10.0 equiv), NaHCO3 (3.0 equiv), toluene,
808C, 72 h, 72%; d) TFA (5.0 equiv), CH2Cl2, 08C to RT, 3 h, 87%;
e) 2-chloro-1-methylpyridinium iodide (1.1 equiv), triethylamine
(3.0 equiv), CH2Cl2, RT, 6 h, 70%. Bn=benzyl, TFA=trifluoroacetic
acid.
II
À
Scheme 3. Transition–state structure for the DBFOX Ph/Zn catalyzed
enantioselective fluorination of malonates 1 to (S)-2.
the fluorination reaction of b-keto esters, which was catalyzed
II
[9a]
À
by Ni /DBFOX Ph.
In the described transformation, the observed chemical
yields and enantioselectivities are excellent and the resulting
chiral 2-fluorinated malonates 2 are potentially versatile
starting materials for the synthesis of biologically important
compounds. In this context, a synthetic application of these
malonates for producing pharmaceutically attractive mole-
cules was investigated. The first of our targets was the
transformation of 2a to fluorinated a-benzyl-b-alanine 4
(Scheme 4). Chemoselective reduction of (S)-2a into 3a was
could be a useful synthon for the synthesis of a fluorinated
analogue of the antibiotic PS-5.[16]
The synthesis of fluoro-alacepril was then examined.
Alacepril is an orally active antihypertensive angiotensin-
converting enzyme (ACE) inhibitor, which was synthesized in
1978[17] and launched in Japan in 1988, along with captopril.
Structurally, alacepril is characterized as a tripeptide-like
compound consisting of l-phenylalanine, l-proline, and 3-
mercapto-(2S)-methylpropionic acid. Captopril and alacepril
both possess a 2-methyl unit with S configuration, which is
indispensable for their ACE inhibitor activities.[18] We were
therefore interested in the previously unknown fluoro-
alacepril as a non-epimerized isostere of alacepril.[19] The
total synthesis of (S)-fluoro-Alacepril was accomplished in
eight steps starting from chiral malonate (S)-2c, based on the
strategy outlined in Scheme 6. Optically active 2-fluoromal-
onate (S)-2c was treated with LiAl(OtBu)3H in THF (85%
yield) followed by tosylation using p-TsCl and pyridine in
CHCl3 to give 12 (81% yield). The l-proline-containing
Scheme 4. Reagents and conditions: a) LiAl(OtBu)3H (5.0 equiv), THF,
À788C to RT, 1 h, 89%; b) p-TsCl (1.2 equiv), pyridine, CHCl3, 08C to
RT, 12 h, 90%; c) NaN3 (3.0 equiv), DMF, 808C, 24 h, 95%; d) Pd/C,
H2, AcOEt, Boc2O, (1.5 equiv), RT, 2 h, 95%. Ts=4-toluenesulfonyl,
DMF=N,N-dimethylformamide, Boc=tert-butoxycarbonyl.
examined by using diisobutylaluminum hydride, LiAlH4, or
LiAl(OtBu)3H.[13] After optimization of the conditions (see
Table S1 in the Supporting Information), the best result was
achieved when using five equivalents of LiAl(OtBu)3H in
THF at À788C, then warming to room temperature giving 3a
in 89% yield. The OH moiety of 3a was then protected using
p-TsCl and pyridine in CHCl3 to give 7 in 90% yield.
Nucleophilic azidation of 7 with NaN3 (95% yield) and
subsequent hydrogenolysis under H2 atmosphere in the
presence of Pd/C and Boc2O in AcOEt afforded the fluoro-
a-benzyl-b-alanine target 4 in 95% yield (Scheme 4).
The utility of 2-fluorinated malonates was next demon-
strated by synthesizing
Scheme 6. Reagents and conditions: a) LiAl(OtBu)3H (5.0 equiv), THF,
À788C to RT, 1 h, 85%; b) p-TsCl (1.2 equiv), pyridine, CHCl3, 08C to
RT, 12 h, 81%; c) TFA (5.0 equiv), CH2Cl2, 08C to RT, 3 h, 90%; d) l-
proline tert-butyl ester (1.05 equiv), EDCI (1.2 equiv), HOBt
(1.2 equiv), diisopropylethylamine (2.0 equiv), CH2Cl2, 08C to RT, 24 h,
67%; e) NaH (3.0 equiv), CH3COSH (3.0 equiv), DMF, 08C to 808C,
4 h, 77%; f) TFA (5.0 equiv), CH2Cl2, 08C to RT, 3 h, 95%; g) l-Phe-
OtBu (1.0 equiv), EDCI (1.3 equiv), HOBt (1.3 equiv), triethylamine
(2.5 equiv), CH2Cl2, 08C to RT, 5 h, 82%; h) TFA (6.0 equiv), CH2Cl2,
RT, 16 h, 73%. EDCI=3-(3-dimethylaminopropyl)-1-ethylcarbodiimide,
HOBt=1-hydroxy-1H-benzotriazole.
a
3-fluorinated b-lactam[5a,b,14]
(Scheme 5). Chemoselective reduction of the malonate
(S)-2b with the LiAl(OtBu)3H procedure mentioned above
gave 3b (80% yield). Subsequent tosylation afforded 9 (85%
yield), which underwent nucleophilic amination using benzyl-
amine to give the b-amino acid derivative 10 (72% yield).
Removal of the tert-butyl ester from 10 with TFA followed by
intramolecular cyclization by the Mukaiyama procedure[15]
afforded the fluorinated b-lactam 5 in 70% yield. This lactam
166
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Chemie
compound 14 was derived from 12 after removal of the tert-
butyl ester with TFA, followed by coupling to l-Pro-OtBu
under standard peptide coupling conditions. Nucleophilic
substitution of CH3COSNa to give 15 followed by TFA
cleavage of the resulting tert-butyl ester gave 16. Subsequent
coupling to l-phenylalanine tert-butyl ester and TFA treat-
ment afforded fluoro-alacepril (6) in good overall yield.
Finally, the optically active fluorinated retroamide iso-
stere 20 was synthesized. Compound 20 is an HIV-1 protease
inhibitor that was prepared by Welch and co-workers from
enantiomerically pure 3-fluoro-2-azetidinones by a ring-
opening reaction.[5a,b,20] However, the synthesis requires
multiple-step transformations including diastereoselective
fluorination of 2-azetidinones. The fluorinated malonate
(S)-2a can be transformed into fluorinated retroamide
isostere 20 in only three steps via unsymmetrical ester-
amide 18 (Scheme 7). Chemoselective ester–amide exchange
Keywords: asymmetric synthesis · chiral Lewis acids ·
desymmetrization · enantioselectivity · fluorination
.
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Scheme 7. Reagents and conditions: a) Zr(OtBu)4 (0.5 equiv), HOAt
(0.5 equiv), BnNH2 (1.0 equiv), toluene, 608C, 24 h, 55%; b) TFA
(10.0 equiv), CH2Cl2, RT, 3 h, 74%; c) l-Val-OBn (1.0 equiv), HOBt
(1.0 equiv), DCC (1.0 equiv), N-methylmorpholine (1.0 equiv), THF,
08C to RT, 24 h, 77%. DCC=1,3-dicyclohexylcarbodiimide, HOAt=
1-hydroxy-azobenzotriazole.
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reaction[21] of (S)-2a successfully proceeded in the presence of
Zr(OtBu)4 to give 18 in good yield. The chemoselectivity
observed is thought to result from the bulkier tert-butyl group
compared to the methyl ester moiety. Subsequent treatment
of 18 with TFA gave the acid 19. Finally, the coupling of 19
with l-Val-OBn proceeded smoothly when effected by DCC
with HOBt treatment to afford the target HIV-1 protease
inhibitor 20 (77% yield).
In conclusion, we have described the first highly enantio-
À
selective fluorination of malonates catalyzed by DBFOX Ph
and Zn(OAc)2. This desymmetrization-like approach for the
preparation of fluorinated chiral building blocks showed
higher enantioselectivity and generality than the correspond-
ing enzymatic approaches.[7] The 2-fluoromalonates 2 can be
easily converted into the corresponding chiral fluorinated
hydroxy esters 3 by chemoselective reduction with LiAl-
(OtBu)3H. The 2-fluoromalonates 2 can also be converted
into the unsymmetrical ester-amides by an chemoselective
ester–amide exchange reaction. All the derivatives are
valuable starting materials for the preparation of pharma-
ceutically attractive molecules,[2–5] and we have demonstrated
the preparation of fluorinated b-amino acids and b-lactams.
The total syntheses of the ACE inhibitor fluoro-alacepril and
the HIV-1 protease inhibitor fluorinated retroamide isostere
were also accomplished.
[9] a) N. Shibata, J. Kohno, K. Takai, T. Ishimaru, S. Nakamura, T.
Toru, S. Kanemasa, Angew. Chem. 2005, 117, 4276 – 4279;
Angew. Chem. Int. Ed. 2005, 44, 4204 – 4207; b) N. Shibata, T.
Ishimaru, T. Nagai, J. Kohno, T. Toru, Synlett 2004, 1703 – 1706;
Received: September 5, 2007
Published online: November 13, 2007
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Communications
c) N. Shibata, T. Ishimaru, M. Nakamura, T. Toru, Synlett 2004,
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