Synthesis of enantiomerically pure 4-polyfluoromethyl-4-hydroxy- homoprolines by intramolecular cyclization of 6-amino-5-polyfluoromethyl-hex-2- enoic acids

Article abstract of DOI:10.1016/j.jfluchem.2014.01.001

An effective route to racemic and enantiopure 4-polyfluoromethyl-4-hydroxy- homoprolines was developed based on readily available 2-alkoxyvinyl- polyfluoromethyl ketones. Key step of the synthesis was a diastereoselective heterocyclization of 6-amino-5-polyfluoromethyl-hex-2-enoic acids under acidic conditions. The absolute configuration of the stereogenic centers was determined by X-ray.

Full text of DOI:10.1016/j.jfluchem.2014.01.001

Accepted Manuscript
Title: Synthesis of enantiomerically pure
4-Polyfluoromethyl-4-hydroxy-, homoprolines by
intramolecular cyclization of
6-Amino-5-polyfluoromethyl-hex-2-enoic acids
Author: Elena N. Shaitanova Igor I. Gerus Valery P. Kukhar
¨
Gunter Haufe
PII:
S0022-1139(14)00002-5
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2014.01.001
FLUOR 8248
To appear in:
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Received date:
Revised date:
Accepted date:
3-10-2013
23-12-2013
2-1-2014
Please cite this article as: E.N. Shaitanova, I.I. Gerus, V.P. Kukhar, G. Haufe,
Synthesis of enantiomerically pure 4-Polyfluoromethyl-4-hydroxy-, homoprolines by
intramolecular cyclization of 6-Amino-5-polyfluoromethyl-hex-2-enoic acids, Journal
of Fluorine Chemistry (2014), http://dx.doi.org/10.1016/j.jfluchem.2014.01.001
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1
Synthesis of enantiomerically pure 4-Polyfluoromethyl-4-hydroxy-
homoprolines by intramolecular cyclization of 6-Amino-5-polyfluoromethyl-
hex-2-enoic acids
Elena N. Shaitanova1, Igor I. Gerus1,* Valery P. Kukhar1, Günter Haufe2
1 Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
Str. Murmanskaya 1, Kiev, 02094, Ukraine
2 Organisch-Chemisches Institut, Universität Münster, Corrensstraße 40, 48149 Münster, Germany
ABSTRACT
An effective route to racemic and enantiopure 4-polyfluoromethyl-4-hydroxy-
homoprolines was developed based on readily available 2-alkoxyvinyl-polyfluoromethyl
ketones. Key step of the synthesis was a diastereoselective heterocyclization of 6-amino-5-
polyfluoromethyl-hex-2-enoic acids under acidic conditions. The absolute configuration of the
stereogenic centers was determined by X-ray
Keywords:
Fluorinated amino acids, Cyclization, Homoprolines, Enones, GABA uptake inhibitors
Introduction
Organofluorine compounds play an important role in medicinal chemistry due to their
enzyme affinity, metabolitic stability, and bioavailability [1]. The replacement of a hydrogen by
a fluorine atom or by a polyfluoroalkyl group is a common strategy to modify the selectivity of
bioactive compounds [2]. The unique properties of fluorine substituents have significant value
for the design of new potential drugs. Among them, analogs of γ-aminobutyric acid (GABA, 4-
aminobutanoic acid) play an important role. GABA is the key inhibitory neurotransmitter of the
central nervous system, which is also responsible for certain neurological disorders. Four
different GABA transporters, i.e. GAT-1, GAT-2, GAT-3 and BGT-1, are known presently [3-
5]. These transporters are differently distributed within the brain and also in other body tissues.
Moreover, their sensitivity against other pharmacological agents is different.
A number of GABA-like uptake inhibitors such as the nipecotic acid derivatives SK&F
89976-A 1 and (±)-cis-SK&F 100591 2 (Fig. 1) have structures different from the GABA core,
but do exhibit similar biological activity [6].
Page 1 of 12

2
OH
R
COOH
COOH
COOH
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
1
2
3
(±) SK&F 100591
R = OH, F
SK&F 89976-A
Fig. 1. GABA-like uptake inhibitors.
Similar cyclic compounds with structures based on pyrrolidine-2-acetic acid (R=H) also
demonstrate affinity to the GABA transporter proteins GAT-1 and GAT-3 [7]. Thus, it was
shown, that the introduction of a hydroxy group at C-4 of the pyrrolidine ring in derivative 3
decreased the ability of GABA to uptake inhibitors at both GAT-1 and GAT-3 [8]. The
replacement of the OH group with fluorine resulted in a similar effect on GAT-1, but less
pronounced in comparison to the 4-hydroxy derivative [9]. Therefore, synthesis of new GABA
uptake inhibitors with high potency and selectivity remains highly desirable. We assume that
combining the hydroxy- and polyfluoromethyl groups at position 5 will increase the potency to
inhibit GABA transporters. Moreover, chiral homoproline has attracted considerable attention
for its use not only in medicinal chemistry but also as potential organocatalysts [10].
Readily available β-alkoxyvinyl polyfluoromethyl ketones 4 have been used as starting
materials to obtain different GABAs 6 bearing polyfluoromethyl groups in β-position, recently
(Scheme 1) [11]. Moreover, enones 4 have been proven to be versatile intermediates to
synthesize a wide variety of biologically interesting compounds [12]. Here we describe simple
and effective syntheses of 4-polyfluoromethyl-4-hydroxy-homoprolines with potential biological
activity.
2. Results and discussion
Recently, we reported the synthesis of polyfluoroalkyl containing aldehydes 5 that can be
used not only as intermediates for β-RF-β-OH GABAs 6 (Scheme 1) [11], but also as precursors
for other polyfluoroalkyl compounds, e.g. carnitine analogs and pyrroles [13].
O
O
ref. [11]
ref. [11]
PGN
H2N
COOH
RF
OEt
RF
OH
RF
OH
6
(R/ S) and (S)-
4
5
(R/ S) and (S)-
(a)
RF = CF3 , CHF2
(b)
;
PGN = N-Phthalimide
Scheme 1. Synthesis of GABAs 6 through aldehydes 5 [11].
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3
In order to synthesize new polyfluoroalkyl containing amino acids 8 (the vinylogues of the
previously synthesized GABAs 6) and to study their reactivity, a synthetic strategy based on the
Wittig reaction of aldehydes 5 to form 7 and subsequent deprotection under acidic conditions
was chosen (Scheme 2).
H2O, H+
120 °C, 4 h
RF
HO
RF
Ph3P=CHCOOEt
5
PGN
COOH
CO2Et
HO
COOH
RF
OH
N
NH2
H
RF = CF3 (a), CHF2 (b);
PGN = N-Phthalimide
9
7
8
Scheme 2. Reaction of aldehydes 5 with stabilized ylide Ph3P=CHCOOEt and hydrolysis of 6-aminoacrylates 7.
Thus, the Wittig reaction of aldehydes 5 with the stabilized ylide Ph3P=CHCO2Et gave the
aminoacrylates 7 as mixtures of Z- and E-isomers in high yields (Table 1). We found that the
ratio of the formed isomers does neither depend on the nature of solvents nor on the nature of the
fluoroalkyl groups. The isomers of the aminoacrylates 7 were separated by column
chromatography. In this reaction the aldehyde 5a (RF = CF3) was used in racemic and
enantiopure forms, while the aldehyde 5b (RF = CHF2) was utilized solely as a racemate.
Table 1
Ratio of isomers and overall yields of aminoacrylates 7.
Product RF
Ratio (%)a
Yieldb
(%)
82
Z-
25
E-
7а
CF3
75
67
7b
CHF2 33
80
a Determined by NMR
b Isolated yield (as mixture of E- and Z- isomers).
Hydrolysis of the corresponding aminoacrylates 7 with 6 molar HCl did not lead to
compounds 8. Instead cyclized, previously unknown homoprolines 9 were formed under these
conditions. In the 19F NMR spectra of the crude reaction mixture only the two signals of the
diastereomeric amino acids 9 and no signals of the intermediates 8 were observed. The
homoprolines 9 were isolated in good yields and diastereoselectivities (Table 2). The
configuration of the starting olefins does not much influence the stereochemistry of the
cyclization step. The latter is practically independent from the number of fluorine atoms in the
RF group, too. An identical ratio of diastereomeric products (about 85:15 for both CF3 and CHF2
compounds) was obtained using either a mixture of isomers or the pure Z- or E-esters 7.
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Separation of the diastereomeric homoprolines 9 in its hydrochloride form runs easily yielding
≥97% pure product after a single recrystallization. Application of the enantiomerically pure ester
(S)-7a as staring compound gave the enantiomerically pure hydrochloride of (4S,2R)-9a as the
major product. The unprotected amino acids 9 were isolated using the ion-exchange resin
Amberlite IRA-120 (Table 2).
Table 2
Cyclization of compounds 7, diastereomeric ratio and overall yields of products 9.
Entry
1
7
RF
Major product
(4R/S,2S/R)-9а 84 : 16
(4S,2R)-9a 85 : 15
Ratio Yield (%)
(R/S)-7а
CF3
82
85
80
2
3
(S)-7a
CF3
(R/S)-7b CHF2 (4R/S,2S/R)-9b 82 : 18
The intramolecular Michael type addition has been extensively used to synthesize nitrogen
heterocycles such as pyrrolidines [14] under basic conditions. In contrast, there are only few
examples for the formation of five- or six-membered nitrogen heterocycles under acidic
conditions from α,β-unsaturated ketones bearing an amide function in remote position [15]. Also
some intermolecular Michael additions of amides or aniline to α,β-unsaturated ketones have been
described [16]. To the best of our knowledge corresponding α,β-unsaturated ω-aminoacid
derivatives have not been used so far. We were not able to detect any hydrolysis intermediate.
However, one could speculate that the phthalimido function is opened to form a phthalic acid
monoamide. Here the nitrogen should be nucleophilic enough [16] to attack an allylic cation
formed from the α,β-unsaturated carboxyl function under strong acidic conditions [17] (Figure
2). This might explain why we did not observe any dependence of the ratio of the formed
diastereomers of 9 from double bond’s stereochemistry in the starting material or from the nature
of the RF group. A weak hydrogen bonding interaction of the OH group with the phthalic acid
monoamide might be responsible for the preferred attack of nitrogen from the Si side with regard
to the double bond. Moreover, quantum chemical calculations of energies of formation for cis-
and trans-9 were performed by several semi-empirical and DFT methods showing only
negligible differences (< 1 kcal/mol) for the final products.
RF
OH
HO
..
NH
OR
PG
PG = Phth; R = Et or H
Fig. 2. Possible transitional structure.
Page 4 of 12

5
Fig. 3. Molecular structure of compound (4S,2R)-10 (ORTEP image)
The configuration of the new stereogenic center was determined by X-ray analysis of the N-
tosyl derivative 10 [18], which was obtained by tosylation of the major diastereomer (4S,2R)-9a
(Fig. 3). The major diastereomer of 9b is assumed to have the same configuration as 9a by the
similarity of NMR spectroscopic data. The most bulky substituents at positions 2 and 4 of the
pyrrolidines 9 are arranged in cis-configuration.
3. Conclusion
In conclusion, we developed a route based on intramolecular Michael heterocyclization to
synthesize new homoprolines 9 bearing hydroxy and polyfluoromethyl groups at position 4. The
diastereoselectivity of the cyclization reaction is moderate. The configuration of the new
stereogenic center was determined by X-ray. Pharmacological studies of these compounds are
currently in a progress and will be disclosed elsewhere in due time.
4. Experimental
Melting points are uncorrected. NMR spectra were recorded on Varian Unity Plus at 400
MHz and Bruker Avance DRX at 500 MHz at 25 °C. TMS (for 1H and 13C NMR) and CCl3F (for
19F NMR) were used as internal standards. IR spectra were recorded on Bruker Vertex 70.
Optical rotation was measured in a 1 dm cuvette using a Perkin Elmer Polarimeter 341. The
progress of reactions was monitored by TLC plates (silica gel 60 F254, Merck). Column
chromatography was carried out on silica gel 60 (Merck No. 109385, particle size 0.040–0.063).
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Ion-exchange chromatography was performed on Amberlite IR-120 by standard techniques. All
starting materials were commercially available and used without further purification.
4.1. General procedure for the Wittig reaction of aldehydes (5a,b)
To a solution of aldehyde 5a (0.951 g, 3.16 mmol) in CH2Cl2 (10 mL) the ylide
Ph3P=CHCO2Et (1.32 g, 3.80 mmol) was slowly added (in 5 minutes by portions) at r.t. under
stirring. The reaction was monitored using TLC. After stirring at r.t. for 8-12 h, the solvent was
evaporated. The reaction mixture was treated with hexane and the solution was passed through
the silicagel to afford the mixtures of Z/E acrylates. The latter was chromatographed and pure
isomers of 7 were obtained.
4.1.1. Ethyl 5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6,6,6-trifluoro-5-hydroxyhex-
2(Z/E)-enoate (7a) was obtained in racemic (R/S)-7a and enantiomerically pure (S)-7a form.
Yield: 0.96 g (82%, as mixture of isomers, ratio of Z- and E-isomers is 25:75).
4.1.2.
Ethyl
(5S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6,6,6-trifluoro-5-
hydroxyhex-2(E)-enoate (7a)
Yield: 0.58g, (60%). Colorless oil, eluent CH2Cl2/MeOH (20:1), Rf = 0.6, [α]D25 −22.45° (c
1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 1.22 (t, 3Н, J = 7.1 Hz), 2.54 (dd, 1Н, J = 15.0 and
8.8 Hz), 2.72 (dd, 1Н, J = 15.0 and 5.6 Hz,), 3.98 (d, 1H, J = 15.0 Hz), 4.10 (d, 1H, J = 15.0 Hz),
4.07 (q, 2H, J = 7.1 Hz), 5.91 (d, 1H, J = 15.6 Hz), 6.99 (m, 1H), 7.78 (m, 2H), 7.89 (m, 2H). 19F
NMR (470.5 MHz, CDCl3) : δ −80.26 (s). Anal. Calcd for C16H14F3NO5: C, 53.79; H, 3.95; N,
3.92; found: C, 53.76; H, 3.73; N, 3.81.
4.1.3. Ethyl (5S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6,6,6-trifluoro-5-
hydroxyhex-2(Z)-enoate (7a)
Yield: 0.18 g, (19 %). White solid, eluent CH2Cl2/MeOH (20:1), Rf = 0.2, [α]D25 +1.77° (c
0.93, CHCl3), mp 61 °С. 1H NMR (500 MHz, CDCl3): δ 1.21 (t, 3H, J = 7.1 Hz), 3.07 (dd, 1Н, J
= 15.0 and 7.2 Hz), 3.18 (dd, 1Н, J = 15.0 and 8.3 Hz), 3.96 (d, 1H, J = 15.1 Hz), 4.14 (d, 1H, J
= 15.1 Hz), 4.16 (q, 2H, J = 7.1 Hz), 5.95 (d, 1H, J = 11.5 Hz), 6.49 (m, 1H), 7.78 (m, 2H), 7.89
(m, 2H). 19F NMR (470.5 MHz, CDCl3): δ −80.05 (s). Anal. Calcd for C16H14F3NO5: C, 53.79;
H, 3.95; N, 3.62; found: C, 53.68; H, 3.76; N, 3.58.
4.1.4. Ethyl (5R/S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6,6-difluoro-5-
hydroxyhex-2(Z/E)-enoate (7b) was obtained from racemic (R/S)-5b. Yield: 0.89 g (80%, as
mixture of isomers, ratio of Z- and E- isomers is 33:67).
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7
4.1.5. Ethyl (5R/S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6,6-difluoro-5-
hydroxyhex-2(E)-enoate (7b)
1
Yield: 0.46 g, (52%). Colorless oil, eluent EtOAc/Et2O (1:1), Rf = 0.82. H NMR (500
MHz, CDCl3): δ 1.23 (t, 3H, J = 7.1 Hz), 2.47 (dd, 1Н, J = 14.4 and 7.7 Hz), 2.56 (dd, 1Н, J =
14.4 and 7.2 Hz), 4.00 (m, 2Н), 4.10 (q, 2Н, J = 7.1 Hz), 5.69 (t, 1Н, J = 56.1 Hz), 5.92 (d, 1Н, J
= 15.4 Hz), 6.99 (м, 1Н), 7.76 (m, 2Н), 7.88 (m, 2Н). 19F NMR (470.5 MHz, CDCl3): δ −131.0
(d, J = 56.1 Hz). Anal. Calcd for C16H15F2NO5: C, 56.64; H, 4.46; N, 4.13; found: C, 56.43; H,
4.36; N, 4.29.
4.1.6. Ethyl (5R/S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6,6-difluoro-5-
hydroxyhex-2(Z)-enoate (7b)
1
Yield: 0.21g, (24%). Colorless oil, eluent EtOAc/Et2O (1:1), Rf = 0.80. H NMR (500
MHz, CDCl3): δ 1.28 (t, 3H, J = 7.1 Hz), 2.91 (dd, 1Н, J = 15.5 and 8.0 Hz), 3.07 (dd, 1Н, J =
15.5 and 8.0 Hz), 4.01 (m, 2Н), 4.17 (q, 2Н, J = 7.1 Hz), 5.76 (t, 1Н, J = 56.1 Hz), 6.00 (d, 1Н, J
= 11.8 Hz), 6.54 (m, 1Н), 7.74 (m, 2Н), 7.86 (m, 2Н). 19F NMR (470.5 MHz, CDCl3): δ −132.00
(d, J = 56.1 Hz). Anal. Calcd for C16H15F2NO5: C, 56.64; H, 4.46; N, 4.13; found: C, 56.45; H,
4.26; N, 4.34.
4.2. General procedure for the hydrolysis of aminoacrylates (7a,b)
A mixture of N-protected aminoacrylates 7a (0.37 g, 1.0 mmol), acetic acid (3.0 mL) and 6
M HCl (30 mL) was heated at 120 °C (bath temperature) for 3–4 h. The reaction mixture was
cooled to room temperature and the solvents were evaporated in vacuum. Water (30 mL) was
added to the residue and extracted with EtOAc (2×30 mL). The aqueous phase was concentrated
in vacuum, passed through Amberlite IR-120 ion exchange resin and washed with distilled
water. Elution of the resin with 3% aq. NH3 afforded the desired homoprolines (R/S)-9a,b,
(4S,2R)-9a with a diastereomeric ratio of about 85:15.
4.2.1. (4S,2R)-4-Hydroxy-4-(trifluoromethyl)pyrrolidin-2-ylacetic acid (9a)
Pure (S)-9a (>99%) was obtained from (S)-7a in 70% yield, after crystallization of its
hydrochloride from MeCN and ion exchange chromatography. Yield: 0.15g, (70%). White solid,
mp 153 ºС, [α]D25 -3.64° (c 0.83, Н2О). 1H NMR (500 MHz, D2O): δ 2.19 (dd, 1H J = 13.6 and
12.2 Hz), 2.38 (dd, 1H, J = 13.6 and 6.1 Hz), 2.85 (dd, 1H, J = 18.1 and 9.1 Hz), 2.94 (dd, 1H, J
= 18.1 and 4.4 Hz), 3.41 (d, 1H, J = 13.1 Hz), 3.68 (d, 1H, J = 13.1 Hz), 4.26 (m, 1H). 19F NMR
(470.5 MHz, D2O): δ −80.67 (s). 13C NMR (125 MHz, D2O): δ 35.14, 37.38, 51.28, 55.20, 78.75
Page 7 of 12

8
(q, J = 25.0 Hz), 124.25 (q, J = 248.0 Hz), 172.25. Anal. Calcd for C7H10F3NO3: C, 39.44; H,
4.73; N, 6.57; found: C, 39.41; H, 4.88; N, 6.45.
4.2.2. (4R/S,2S/R)-4-Hydroxy-4-(difluoromethyl)pyrrolidin-2-ylacetic acid (9b)
Compound 9b was obtained from (R/S)-7b, in >99% purity (after crystallization of its
hydrochloride from MeCN and ion exchange chromatography.). Yield: 0.14 g, (68%). White
1
solid, mp 160 ºС. H NMR (500 MHz, D2O): δ 2.10 (dd, 1H, J = 14.1 and 11.6 Hz), 2.23 (dd,
1H, J = 14.1 and 6.8 Hz), 2.80 (dd, 1H, J = 18.1 and 9.2 Hz,), 2.91 (dd, 1H, J = 18.1 and 3.7 Hz),
19
3.28 (d, J = 13.0 Hz), 3.53 (d, J = 13.0 Hz), 4.21 (m, 1Н), 5.93 (t, J = 56.0 Hz, 1Н). F NMR
(470.5 MHz, D2O): δ −130.74 (dd, 1F, J = 286.1 and 55.1 Hz), −129.88 (dd, 1F, J = 286.1 and
56.0 Hz). 13C NMR (125 MHz, D2O): δ 35.44, 37.18, 51.04, 55.27, 78.81 (t, J = 23.0 Hz), 114.53
(t, J = 245.0 Hz), 173.80. Anal. Calcd for C7H11F2NO3: C, 43.08; H, 5.68; N, 7.18; found: C,
42.88; H, 5.38; N, 7.40.
4.3. (4S,2R)-2-(4-Hydroxy-1-tosyl-4-(trifluoromethyl)pyrrolidin-2-yl)acetic acid (10)
The amino acid (4S,2R)-9a (0.1 g, 0.47 mmol) was dissolved in H2O (1 mL). To resulting
solution p-toluenesulphonyl chloride (0.09 g, 0.46 mmol) in Et2O (2 mL) was added and stirred
at 0 °C. Then potassium carbonate (0.05 g, 0.46 mmol) was added. The mixture was stirred at 0
°C until completion (TLC, about 3 h), diluted with ether (2 mL) and organic phase separated.
Then washed with 2M HCl (2×5 mL), consecutively with water, dried over magnesium sulfate,
filtered and concentrated in vacuo. Yield: 0.12g, (74%). White solid (from CHCl3/hexane, 2:1),
mp 92 ºС. 1H NMR (CDCl3): δ 2.12 (dd, 1H, J = 13.3 and 10.0 Hz), 2.32 (dd, 1H, J = 13.3 and
6.3 Hz), 2. 43 (s, 3H), 2.74 (dd, 1H, J = 17.0 and 9.1 Hz), 2.34 (dd, 1H, J = 17.1 and 4.0 Hz),
3.52 (d, 1H, J = 13.3 Hz), 3.69 (d, 1H, J = 13.3 Hz), 4.17 (m, 1H), 7.34 (d, 2H, J = 7.9 Hz), 7.75
(d, 2H, J = 7.9 Hz). Anal. Calcd for C13H14F3NO5S: C, 44.19; H, 3.99; N, 3.96; found: C, 44.22;
H, 3.97; N, 3.90.
Acknowledgment
This work was supported by Deutsche Forschungemeinschaft (Ha 2145/9-1; AOBJ: 560896).
We express our gratitude to Alexander N. Chernega (Institute of Organic Chemistry, Kiev,
Ukraine) for performing the X-ray diffraction study.
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[13] (a) E. N. Shaitanova, I. I. Gerus, V. P. Kukhar, Tetrahedron Lett. 49 (2008) 1184–1187; (b)
E. N. Shaitanova, I. I. Gerus, L. A. Metelitsa, L. L. Charochkina, Ukr. Bioorg. Acta. 5
(2007) 43-51.
[14] For some examples see: (a) K. Shishido, Y. Sukegawa, K. Fukumoto, Heterocycles 24
(1986) 641-645; (b) N. Knouzi, M. Vaultier, L. Toupet, R. Carrie, Tetrahedron Lett. 28
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(1987) 1757-1760; (c) S. J. F. Macdonald, D. J. Belton, D. M. Buckley, J. E. Spooner, M.
S. Anson, L. A. Harrison, K. Mills, R. J. Upton, M. D. Dowle, R. A. Smith, C. R. Molloy,
C. Risley, J. Med. Chem. 41 (1998) 3919–3922; (d) E. C. Carlson, L. K. Rathbone, H.
Yang, N. D. Collett, R. G. Carter, J. Org. Chem. 73 (2008) 5155-5158.
[15] (a) D. Bland, G. Chambournier, V. Dragan, D. J. Hart, Tetrahedron 55 (1999) 8953-8966;
(b) I. J. McAlpine, R. W. Armstrong, Tetrahedron Lett. 41 (2000) 1849-1853.
[16] T. C. Wabnitz, J. B. Spencer, Org. Lett. 5 (2003) 2141-2144.
[17] H. Fuwa, N. Ichinokawa, K. Noto, M. Sasaki, J. Org. Chem. 77 (2012) 2588-2607.
[18] Crystallographic data (excluding structure factors) for (4S,2R)-10 have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC
932862. Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: +44 1223 336033 or e-mail:
deposit@ccdc.ca.
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HO
RF
HO
RF
H2O, H+
PGN
CO2Et
COOH
RF OH
COOH
N
NH2
H
RF = CHF2, CF3
de = 70%
yield 80-82%
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The first synthesis of racemic and enantiopure 4-polyfluoromethyl-4-hydroxy-
homoprolines
The synthesis of polyfluoromethyl containing 6-aminoacrylates
The example of intramolecular heterocyclization under acidic conditions
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