Crystallization-induced dynamic resolution of fox chiral auxiliary and application to the diastereoselective electrophilic fluorination of amide enolates

Article abstract of DOI:10.1021/jo400210j

A highly efficient crystallization-induced dynamic resolution (CIDR) of trans-Fox (fluorinated oxazolidine) chiral auxiliary is reported. This chiral auxiliary was used for highly diastereoselective (>98% de) electrophilic fluorination of amide enolates. After removal of the chiral auxiliary, highly valuable enantiopure α-fluorocarboxylic acids and β-fluoroalcohols are obtained.

Full text of DOI:10.1021/jo400210j

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Note
Crystallization Induced Dynamic Resolution of Fox
Chiral Auxiliary and Application to the Diastereoselective
Electrophilic Fluorination of Amide Enolates
Hodney Lubin, Christophe Dupuis, Julien Pytkowicz, and Thierry Brigaud
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400210j • Publication Date (Web): 12 Mar 2013
Downloaded from http://pubs.acs.org on March 15, 2013
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Crystallization Induced Dynamic Resolution of Fox Chiral Auxiliary and
Application to the Diastereoselective Electrophilic Fluorination of Amide
Enolates
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Hodney Lubin, Christophe Dupuis, Julien Pytkowicz and Thierry Brigaud*
Laboratoire " Synthèse Organique Sélective et Chimie bioOrganique " (SOSCO), Université
de Cergy-Pontoise. 5 Mail Gay-Lussac 95000 Cergy-Pontoise cedex, France
E-mail: thierry.brigaud@u-cergy.fr
Table of Contents/Abstract Graphic:
Abstract:
A highly efficient crystallization induced dynamic resolution (CIDR) of trans-Fox
(fluorinated oxazolidine) chiral auxiliary is reported. This chiral auxiliary was used for highly
diastereoselective (>98% de) electrophilic fluorination of amide enolates. After removal of
the chiral auxiliary, highly valuable enantiopure α-fluorocarboxylic acids and β-
fluoroalcohols are obtained.
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Chiral fluorinated compounds are playing an increasing role in the design of
pharmacologically relevant molecules.1-3 Several methods are reported in the literature for
their stereoselective syntheses involving nucleophilic, electrophilic or radical
methodologies.4-11 For the specific case of the stereoselective synthesis of α-fluorocarbonyl
compounds, the electrophilic fluorination of an enolizable carbonyl group is obviously the
most direct method. To this end, catalytic and chiral auxiliary-based methodologies have been
reported for the electrophilic fluorination of enols or enolates. Davis et al.12-15 and others16-18
reported the efficient diastereoselective fluorination of oxazolidinone-based lithium amide
enolates using N-fluoro-o-benzenedisulfonimide (NFOBS) or N-fluorobenzenesulfonimide
(NFSI) as the fluorinating reagent. Although the diastereoselectivity of the fluorination
reaction was good (87% to 97% de) a decreased of enantioselectivity was observed after the
removal of the oxazolidinone chiral auxiliary giving enantioenriched α-fluorocarboxylic acids
(69% to 90% ee) and β-fluoroalcohols (89% to >95% ee). However this epimerization could
be controlled when the α-fluorocarboximide was converted into a Weinreb amide precursor of
α-fluoroketones.19 The diastereoselective synthesis of quaternarized α-fluorocarbonyl
compounds using oxazolidinone chiral auxiliaries has also been more recently reported.20-21
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In the course of our investigations on a fluorinated oxazolidine (Fox) as chiral auxiliary22-27
we decided to consider its performance for the challenging electrophilic fluorination of amide
enolates. Moreover, conversely to oxazolidinones, it was anticipated that the non-basic
conditions suitable for the removal of this chiral auxiliary would lead to chiral α-
fluorocarboxylic acids and β-fluoroalcohols without decrease of enantioselectivity. In order to
enlarge the scope of the use of this attracting chiral auxiliary, we had first to optimise its large
scale preparation. Indeed, until now the fluorinated oxazolidines (Fox) prepared by
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condensation of fluoral or its hemiacetal with (R)-phenylglycinol28 were obtained as a 60:40
to 70:30 mixtures of trans and cis diastereomers and the separation of both diastereomers was
quite difficult. However this was not a redhibitory limitation for amide enolates chemistry
because the trans and cis N-acyl oxazolidines were very conveniently separated by silica gel
chromatography.22 However, we established that in fact the only trans-Fox was an efficient
chiral auxiliary because of its C2 pseudosymmetry.22,23 As a consequence, the cis N-acyl
oxazolidines were useless. As a major improvement in the use of the Fox chiral auxiliary, we
report herein an efficient and scalable procedure for the selective synthesis of the trans-Fox
chiral auxiliary. We also report its use for the highly diastereoselective electrophilic
fluorination of amide enolates.
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The Fox chiral auxiliary was obtained in high yield (91%) by condensation of (R)-
phenylglycinol and fluoral ethyl hemiacetal as a 62:38 trans/cis diastereomeric mixture
(Scheme 1).28 The two diastereomers are configurationally stable in neutral medium but their
separation proved to be very difficult. In order to increase the ratio of trans-Fox we
envisioned to shift the equilibrium in favor of the trans-Fox in acidic medium. A large
screening of acids (AcOH, PPTS, PTSA, TFA) and solvent mixtures (cyclohexane, Et2O,
AcOEt, MeOH, EtOH) was considered. In most cases, a diastereomeric mixture of trans- and
cis-Fox salts was obtained. However excellent results were obtained when the epimerization
was carried out with p-toluenesulfonic acid (PTSA) in AcOEt (Scheme 1). In these
conditions, the only trans-Fox diastereomer crystallized to give a pure p-toluenesulfonate salt
of trans-Fox in 79% yield after filtration. This diastereomeric enrichment is a nice illustration
of the crystallization induced dynamic resolution (CIDR) concept.29-35 After neutralization of
the p-toluenesulfonate salt, the trans-Fox was obtained in excellent yield (99%) and large
scale (27.75 g).
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Scheme 1. Crystallization induced dynamic resolution (CIDR) of the trans-Fox chiral
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auxiliary
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After N-acylation of the trans-Fox according to our previously reported procedures,22,23 the
electrophilic fluorination reactions of the sodium enolates of N-acyloxazolidines 1a-f were
investigated (Table 1). No reaction occurred when Selectfluor or N-fluoro-2,6-
dichloropyridinium tetrafluoroborate (NFDPT) were used (Table 1, entries 1 and 2). However
N-fluorobenzenesulfonimide (NFSI) showed to be a suitable electrophilic fluorine source. The
electrophilic fluorination of amides 1a-c occurred in 67-73% yield with a complete
diastereoselectivity (>98% de)36 (Table 1, entries 3-5). The reactions with more sterically
hindered amide enolates was also achieved with an excellent diastereoselectivity (>98% de)
but in lower yields (Table 1, entries 6 and 7). In order to have access to highly valuable α-
amino-α-fluoro compounds, the electrophilic fluorination reaction was applied to the α-
amino-substrate 1f. The expected fluorinated compound 2f was obtained in 73% yield with a
total diastereoselectivity (Table 1, entry 8).
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Table 1. α-fluorination of trans-Fox amide enolates
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Entry F+ agent (equiv)
R
Me
Me
Me
Ph
Yield (%)a de (%)b
Product
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4e
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Selectfluor (2)
NFDPTc (1.5)
NFSId (2)
NFSI (2)
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>98
>98
>98
>98
>98
>98
2a (R)
2b (R)
2c (R)
2d (R)
2e (R)
2f (R)
NFSI (2)
Bn
nBu
iPr
NFSI (2)
NFSI (2)
NFSI (2)
(Bn)2NCH2 73
aYield of pure isolated product. bDetermined by 1H and 19F NMR on the crude mixture. cN-fluoro-2,6-
dichloropyridinium tetrafluoroborate. d N-fluorobenzenesulfonimide. e The enolate was generated from 1.1 equiv
of NaHMDS. The use of 2 equiv of NaHMDS gave 2b in 13% yield and the corresponding difluorinated
compound in 60% yield.
The removal of the trans-Fox chiral auxiliary and its recovery without epimerization of the
target α-fluorocarbonyl compounds is a crucial step. The α-fluoro amides 2c and 2f were
chosen as representative starting material to study this transformation. According to our
previously reported procedure26 the LiAlH4 reduction of 2c and 2f followed by a slightly
acidic treatment gave the α-fluoro aldehydes 4c and 4f together with the trans-Fox chiral
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auxiliary (Scheme 2). The synthesis of similar α-fluoroaldehydes in enantioenriched form has
already been reported by means of organocatalytic methods.37-41 The hemiaminals 3c and 3f
were identified to be the intermediates of the reaction.
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Scheme 2. Removal of the trans-Fox chiral auxiliary.
As the α-fluoroaldehydes 4c,f and the trans-Fox chiral auxiliary could not be easily separated
by silica gel chromatography at this stage, we decided to oxidize the aldehydes 4c,f into the
coresponding α-fluorocarboxylic acids without separation of the intermediate
aldehyde/oxazolidine mixture. Hence, the amides 2c,f were submitted to a LiAlH4
reduction/acidic hydrolysis/oxidation sequence to give enantiopure α-fluorocarboxylic acids
5c and 5f in 89% and 71% yield respectively (Scheme 3). The trans-Fox chiral auxiliary was
recovered in 73-74% yield. The excellent enantiomeric purity of 5c and 5f was confirmed by
chiral HPLC analysis or NMR analysis of the corresponding (S)-phenylethylamide derivative.
The (R) configurations were assigned by correlation with the corresponding aminoalcohols
configurations (vide infra).
Scheme 3. Two-step procedure for the synthesis of enantiopure carboxylic acids 5c,f with an
efficient recovery of the chiral auxiliary trans-Fox.
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According to a similar strategy the α-fluoroamides 2c,f were submitted to a LiAlH4
reduction/hydrolysis/NaBH4 reduction sequence to provide the β-fluoroalcohols 6c,f without
isolation of the intermediate α-fluoroaldehydes 4c,f (Scheme 4). The enantiopure β-
fluoroalcohols 6c,f were obtained in 77% yield. The (R) configurations of 6c and 6f were
assigned by comparison of their optical rotation value with literature data.39,40,42 The
enantiopurity of the fluoroalcohols 6c and 6f was confirmed by formation of their
diastereomerically pure (R)-Mosher’s esters.
Scheme 4. Two-step procedure for the synthesis of enantiopure β-fluoroalcohols 6c,f.
The re face fluorination of the chiral enolates providing the (R) configuration of the newly
formed stereocentre is consistent with our previously reported experimental and theoretical
studies on the alkylation22,23 and the hydroxylation26 of Fox-amide enolates. We propose a
chelated transition state presenting both Na•••F and Na•••O interactions leading to a very
highly diastereoselective carbone-fluorine bond formation (Figure 1). The involvement of the
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Na•••O (sulfonamide oxygen) interaction activating the NFSI reagent is crucial. This could
explain the reason why no fluorination reactions occurred with Selectfluor or N-
fluoropyridinium salt.
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Figure 1. Postulated transition state leading to the re face fluorination of the enolate.
In summary, we have reported a highly efficient preparation of trans-Fox chiral auxiliary
based on the crystallization induced dynamic resolution (CIDR) concept. This chiral auxiliary
allowed the electrophilic fluorination of amide enolates with an outstanding
diastereoselectivity. Enantiopure α-fluorocarboxylic acids and β-fluoroalcohols were obtained
after the removal and the recovery of the chiral auxiliary.
Experimental Section:
Crystallization induced dynamic resolution of trans-Fox. PTSA.H2O (46.44 g, 244.1
mmol, 1.5 equiv) was dissolved in ethyl acetate (200 mL). The solvent was partially removed
under reduced pressure. Toluene (250 mL) was added and all the solvents were removed. The
dry PTSA was dissolved in ethyl acetate (500 mL) under argon atmosphere. Under vigorous
stirring, a 62:38 diastereomeric mixture of oxazolidines trans-Fox and cis-Fox (35.35 g,
163.8 mmol, 1.0 equiv) in ethyl acetate (80 ml) was added dropwise. The precipitate was
filtrated and washed with a minimum amount of ethyl acetate and the mother liquors were
concentrated
to
induce
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precipitation.
The
sequence
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precipitation/filtration/concentration was repeated at least 3 times to furnish the p-
toluenesulfonate salt of trans-Fox (50.25 g, 129.1 mmol, 79%) as a white powder.
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The mother liquors were treated with a saturated K2CO3 solution and extracted with ethyl
acetate. The organic layers were dried over MgSO4, filtrated and concentrated under reduced
pressure to afford a remaining mixture of oxazolidines trans-Fox and cis-Fox (7.070 g, 32.55
mmol, 20%, 78/22 dr) as a yellow oil. This mixture of oxazolidines can be further submitted
to another crystallization induced dynamic resolution sequence.
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(2S,4R)-4-phenyl-2-trifluoromethyloxazolidine (trans-Fox). To a suspension of the p-
toluenesulfonate salt of trans-Fox (50.20 g, 128.9 mmol, 1.0 equiv) in ethyl acetate (375 mL)
was added a saturated solution of K2CO3 (125 mL). After complete solubilization of the
precipitate, water (125 mL) was added and the aqueous layers are carefully extracted with
ethyl acetate. The organic layers were combined, dried over MgSO4, filtered and concentrated
under reduced pressure. The enantiopure (2S,4R)-4-phenyl-2-trifluoromethyloxazolidine
trans-Fox (27.75 g, 127.8 mmol, 99%), was obtained as a colorless oil.28
Starting N-acylated oxazolidines (1a-f). The starting N-acylated oxazolidines 1a, 1c, 1e and
1f were prepared according to our previously reported procedures starting from enantiopure
trans-Fox and the corresponding acyl chloride.22,23
(2S,4R)-4-phenyl-3-phenylacetyl-2-trifluoromethyloxazolidine (1b). Obtained from
enantiopure oxazolidine trans-Fox (1.394 g, 6.42 mmol, 1.0 equiv) and phenylacetyl chloride
(1.11 mL, 8.34 mmol, 1.3 equiv). Purification by silica gel chromatography
(cyclohexane/ethyl acetate 95/5) yielded the pure amide 1b (1.719 g, 10.30 mmol, 78%) as a
white solid. m.p. = 94-95 °C; [α]D –49.9 (c = 0.45, CHCl3); IR 3029, 2925, 2168, 1967, 1672,
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1492, 1453, 1375, 1280, 1144, 1102, 984, 929, 897, 755, 690 cm–1; H NMR (400 MHz) δ
3.31 (d, 1H, J = 15.8 Hz), 3.36 (d, 1H, J = 15.8 Hz), 4.01 (d, 1H, J = 8.7 Hz), 4.59 (dd, 1H, J
= 8.70, 6.4 Hz), 4.84 (d, 1H, J = 6.4 Hz), 6.16 (q, 1H, JH-F = 5.1 Hz), 6.93–6.95 (m, 2H), 7.19-
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7.27 (m, 6H), 7.36–7.44 (m, 2H); 13C NMR (100.5 MHz) δ 42.7, 60.3, 76.5, 85.3 (q, J = 35.1
Hz), 123.4 (q, J = 289.5 Hz), 125.6, 127.1, 128.6, 128.8, 128.9, 129.7, 133.6, 141.4, 171.3;
19F NMR (376.2 MHz) δ –80.3 (d, J = 5.1 Hz); HRMS (EI+, direct inlet probe) m/z: [M+]
Calcd for C18H16F3NO2 335.1133; Found 335.1142.
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(2S,4R)-3-hexanoyl-4-phenyl-2-trifluoromethyloxazolidine
(1d).
Obtained
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enantiopure oxazolidine trans-Fox (3.000 g, 13.81 mmol, 1.0 equiv) and hexanoyl chloride
(3.52 mL, 24.86 mmol, 1.8 equiv). Purification by silica gel chromatography
(cyclohexane/ethyl acetate 95/5) yielded the pure amide 1d (4.094 g, 12.98 mmol, 94%) as a
pale yellow solid. m.p. = 47-48 °C; [α]D –61.3 (c = 1.16, CHCl3); IR 2945, 2867, 1658, 1457,
1400, 1280, 1148, 1099, 984, 921, 838, 747, 689 cm–1; 1H NMR (400 MHz) δ 0.78 (t, 1H, J =
7.1 Hz), 1.02–1.16 (m, 4H), 1.30 (dtdd, 1H, J = 14.0, 7.1 Hz, 6.4 Hz, 6.2 Hz), 1.49 (dddt, 1H,
J = 14.0, 8.7, 8.5, 7.1 Hz), 1.81 (ddd, 1H, J = 15.2, 8.7, 6.2 Hz), 2.13 (ddd, 1H, J = 15.2, 8.5,
6.4 Hz), 4.07 (d, 1H, J = 8.7 Hz), 4.69 (dd, 1H, J = 8.7, 6.4 Hz), 4.99 (d, 1H, J = 6.4 Hz), 6.14
(q, 1H, JH-F = 5.1 Hz), 7.15–7.40 (m, 5H);.13C NMR (100.5 MHz) δ 14.0, 22.4, 24.3, 31.2,
35.9, 60.8, 76.6, 85.1(q, J = 34.5 Hz), 123.5 (q, J = 288.5 Hz), 125.7, 128.7, 129.5, 141.6,
19
170.6; F NMR (376.2 MHz) δ –80.69 (d, J = 5.1 Hz); HRMS (EI+, direct inlet probe) m/z:
[M+] Calcd for C16H20F3NO2 315.1446; Found 315.1441.
General procedure for the synthesis of fluorinated amides (2a-f). To a solution of the
amide 1a-f (1.00 mmol, 1.0 equiv) in THF (8 mL) under argon at –78 °C was added a solution
of NaHMDS (1.00 mL, 2.0 M in THF, 1.00 mmol, 2.0 equiv). The reaction mixture was
stirred at –78 °C for 45 min. Then NFSI (0.632 g, 2.00 mmol, 2.0 equiv) was added. The
reaction mixture was stirred at –78 °C for 18 h. and quenched with a saturated aqueous NH4Cl
solution (7 mL). The aqueous layer was extracted three times with ethyl acetate. The organic
layers were combined and dried over MgSO4, filtered and concentrated under reduced
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pressure. The crude product was purified by flash chromatography (cyclohexane/ethyl acetate
95/5) to afford the pure fluorinated product. Because of cis/trans amide conformers
occurrence, NaH epimerization reactions of compounds 2 were performed in order to
discriminate cis/trans conformers and potential diastereomers.
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(2S,4R)-3-[(R)-2-fluoropropanoyl]-4-phenyl-2-trifluoromethyloxazolidine (2a). Obtained
from the N-acylated oxazolidine 1a (0.274 g, 1.00 mmol, 1.0 equiv) using the general
procedure. After purification by silica gel chromatography (cyclohexane/ethyl acetate 95/5)
the pure fluorinated product 2a (0.195 g, 0.67 mmol, 67%, > 98% de) was obtained as a white
solid. m.p. = 47-49 °C; [α]D –41.0 (c = 2.0, CHCl3); IR 2984, 2164, 1972, 1670, 1494, 1455,
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1413, 1320, 1281, 1142, 1093, 1031, 980, 932, 849, 756, 688 cm–1; H NMR (400 MHz)
(Major conformer) δ 1.33 (dd, 3H, JH-F = 25.0 Hz and J = 6.4 Hz), 4.10 (d, 1H, J = 8.5 Hz),
4.25 (dq, 1H, JH-F = 46.7 Hz and J = 6.4 Hz), 4.70 (dd, 1H, J = 8.5, 6.4 Hz), 5.29 (d, 1H, J =
6.4 Hz), 6.18 (q, JH-F = 5.0 Hz), 7.19–7.26 (m, 2H), 5.31–5.40 (m, 3H);.13C NMR (100.5
2
4
MHz) (Major conformer) δ 17.1 (d, JC-F = 22.0 Hz), 60.3 (d, JC-F = 7.7 Hz), 76.8, 85.6 (q,
1
2JC-F = 34.5 Hz), 87.3 (d, JC-F = 179.23 Hz), 123.3 (q, J = 288.5 Hz), 126.1, 128.9, 129.5,
141.0, 170.3 (d, J = 20.1 Hz); 19F NMR (376.2 MHz) (Major conformer) δ –184.4 (dq, 1F, J =
46.7, 25.0 Hz), –81.0 (d, 3F, J = 5.0 Hz); HRMS (EI+, direct inlet probe) m/z: [M+] Calcd for
C13H13F4NO2 291.0882; Found 291.0890; Anal. Calcd for C13H13F4NO2 C, 53.61; H, 4.50; N,
4.81. Found: C, 53.55; H, 4.33; N, 4.80.
(2S,4R)-3-[(2R)-2-fluoro-2-phenylacetyl]-4-phenyl-2-trifluoromethyloxazolidine
(2b).
Obtained from the N-acylated oxazolidine 1b (0.336 g, 1.00 mmol, 1.0 equiv) using the
general procedure. The enolate was generated with 1.1 equiv of NaHMDS (0.55 mL, 2.0 M in
THF, 1.1 mmol, 1.1 equiv). After purification by silica gel chromatography
(cyclohexane/ethyl acetate 95/5) the pure fluorinated product 2b (0.259 g, 0.73 mmol, 73%,
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>98% de) was obtained as a white solid. m.p. = 82-83 °C; [α]D –73.7 (c = 1.0, CHCl3); IR
3037, 2165, 2026, 1664, 1495, 1414, 1317, 1269, 1144, 1104, 1035, 976, 925, 843, 761, 687,
632 cm–1; 1H NMR (400 MHz) (Major conformer) δ 4.14 (bs, 1H), 4.76 (bs, 1H), 5.12 (d, 1H,
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JH-F = 46.5 Hz), 5.45 (bs, 1H), 6.24 (bs, 1H), 7.04–7.47 (m, 10H); C NMR (100.5 MHz)
(Major conformer) δ 60.7, 76.8, 85.8 (q, J = 36.4 Hz), 91.0 (d, J = 185.0 Hz), 123.3 (q, J =
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289.5 Hz), 126.1, 127.7 (2C), 128.5, 128.9, 129.6, 134.1, 141.3, 169.1 (d, J = 22.0 Hz); F
NMR (376.2 MHz) (Major conformer) δ –176.2 (d, 1F, J = 46.5 Hz), –80.9 (bs, 3F); HRMS
(EI+, direct inlet probe) m/z: [M+] Calcd for C18H15F4NO2 353.1039; Found 353.1034; Anal.
Calcd for C18H15F4NO2 C, 61.19; H, 4.28; N, 3.96. Found: C, 60.99; H, 4.49; N, 4.00.
(2S,4R)-3-[(2R)-2-fluoro-3-phenylpropanoyl]-4-phenyl-2-trifluoromethyloxazolidine
(2c). Obtained from the N-acylated oxazolidine 1c (0.350 g, 1.00 mmol, 1.0 equiv) using the
general procedure. After purification by silica gel chromatography (cyclohexane/ethyl acetate
95/5) the pure fluorinated product 2c (0.268 g, 0.73 mmol, 73%, > 98% de) was obtained as a
white solid. m.p. = 96-97 °C; [α]D –52.9 (c = 1.02, CHCl3); IR 3024, 2923, 2168, 1969, 1745,
1659, 1493, 1448, 1396, 1324, 1276, 1149, 1109, 1079, 1024, 977, 927, 840, 751, 691, 636
cm–1; 1H NMR (400 MHz) δ 3.02 (ddd, 1H, JH-F = 31.7 Hz, J = 14.9, 4.2 Hz), 3.10 (ddd, 1H,
JH-F = 23.0 Hz, J = 14.9, 7.8 Hz), 4.09 (d, 1H, J = 8.7 Hz), 4.42 (ddd, 1H, JH-F = 47.3 Hz, J =
7.8, 4.2 Hz), 4.68 (dd, 1H, J = 8.7, 6.6 Hz), 5.30 (d, 1H, J = 6.4 Hz), 6.23 (q, JH-F = 5.1 Hz),
7.02–7.05 (m, 2H), 7.17–7.28 (m, 5H), 7.30–7.39 (m, 3H); 13C NMR (100.5 MHz) δ 37.5 (d,
J = 21.1 Hz), 60.4 (d, J = 7.7 Hz), 76.8 (C5), 85.6 (q, J = 36.4 Hz), 90.6 (d, J = 185.0 Hz),
123.2 (q, J =288.5 Hz), 125.9, 126.9, 128.5, 128.8, 129.5, 135.6, 141.2, 169.5 (d, J = 21.1
Hz); 19F NMR (376.2 MHz) (Major conformer) δ –190.1 (ddd, 1F, J = 47.3, 31.7, 23.0 Hz), –
80.9 (d, 3F, J = 5.1 Hz); HRMS (EI+, direct inlet probe) m/z: [M+] Calcd for C19H17F4NO2
367.1195; Found 367.1205; Anal. Calcd for C19H17F4NO2 C, 62.12; H, 4.66; N, 3.81. Found:
C, 62.14; H, 4.42; N, 4.03.
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(2S,4R)-3-[(R)-2-fluorohexanoyl]-4-phenyl-2-trifluoromethyloxazolidine (2d). Obtained
from the N-acylated oxazolidine 1d (0.316 g, 1.00 mmol, 1.0 equiv) using the general
procedure. After purification by silica gel chromatography (cyclohexane/ethyl acetate 95/5)
the pure fluorinated product 2d (0.115 g, 0.35 mmol, 35%, >98% de) was obtained as a white
solid. m.p. = 67-68 °C; [α]D –33.0 (c = 2.2, CHCl3); IR 2961, 1682, 1390, 1280, 1181, 1149,
848, 702, 685 cm–1; 1H NMR (400 MHz) δ 0.82 (t, 3H, J = 7.0 Hz), 1.13–1.33 (m, 4H), 1.64–
1.87 (m, 2H), 4.11 (d, 1H, J = 8.7 Hz), 4.14 (ddd, JH-F = 47.2 Hz, J =7.6, 4.1 Hz), 4.70 (dd,
1H, J = 8.7, 6.6 Hz), 5.14 (d, 1H, J = 6.6 Hz), 6.21 (q, JH-F = 5.1 Hz), 7.19–7.40 (m, 5H);.13C
NMR (100.5 MHz) δ 13.9, 22.3, 26.3, 31.0 (d, J = 21.1 Hz), 60.4 (d, J = 9.6 Hz), 76.8, 85.6
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(q, J = 35.5 Hz), 90.5 (d, JC-F = 183.1 Hz), 123.3 (q, JC-F = 288.5 Hz), 126.0, 128.8, 129.5,
141.3, 170.3 (d, J = 21.1 Hz); 19F NMR (235.3 MHz) δ –192.0 (ddd, 1F, J = 47.2, 30.6, 23.5
Hz), –81.1 (d, 3F, J = 4.7 Hz); HRMS (EI+, direct inlet probe) m/z: [M+] Calcd for
C16H19F4NO2 333.1352; Found 333.1367; Anal. Calcd for C16H19F4NO2 C, 57.65; H, 5.75; N,
4.20. Found: C, 58.25; H, 5.90; N, 4.11.
(2S,4R)-3-[(2R)-2-fluoro-3-methylbutanoyl]-4-phenyl-2-trifluoromethyloxazolidine (2e).
Obtained from the N-acylated oxazolidine 1e (0.302 g, 1.00 mmol, 1.0 equiv) using general
procedure. After purification by silica gel chromatography (cyclohexane/ethyl acetate 95/5)
the pure fluorinated product 2e (0.092 g, 0.29 mmol, 29%, > 98% de) was obtained as a white
solid. m.p. = 52-53 °C; [α]D –37.1 (c = 1.06, CHCl3); IR 2969, 2928, 2164, 2028, 1672, 1458,
1370, 1273, 1183, 1143, 1111, 1041, 993, 937, 844, 751, 693, 645 cm–1; 1H NMR (400 MHz)
(Major conformer) δ 0.84 (d, 3H, J = 6.9 Hz), 0.89 (d, 3H, J = 6.6 Hz), 2.30 (dqqd, 1H, JH-F
=
30.5 Hz, J = 6.9, 3.1 Hz), 3.97 (dd, 1H, JH-F = 47.4 Hz, J = 3.1 Hz), 4.08 (d, 1H, J = 8.7 Hz),
4.68 (dd, 1H, J = 8.7, 6.2 Hz), 5.36 (d, 1H, J = 6.2 Hz), 6.25 (q, 1H, JH-F = 5.3 Hz), 7.19–7.39
(m, 5H);.13C NMR (100.5 MHz) (Major conformer) δ 15.3 (d, J = 5.8 Hz), 18.6 (d, J = 2.9
Hz), 30.6 (d, J = 20.1 Hz), 60.7 (d, J = 10.5 Hz), 76.9, 85.5 (q, J = 34.5 Hz), 94.6 (d, J =
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188.8 Hz), 123.4 (q, J = 288.5 Hz), 125.9, 128.5, 129.3, 141.7, 172.5 (d, J = 21.1 Hz); F
NMR (376.2 MHz) (Major conformer) δ –205.0 (dd, 1F, J = 47.4, 30.5 Hz), –81.3 (d, 3F, J =
5.3 Hz); HRMS (EI+, direct inlet probe) m/z: [M+] Calcd for C15H17F4NO2 319.1195; Found
319.1211; Anal. Calcd for C15H17F4NO2 C, 56.42; H, 5.37; N, 4.39. Found: C, 56.15; H, 5.25;
N, 4.38.
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(2S,4R)-3-[(2R)-3-dibenzylamino-2-fluoropropanoyl]-4-phenyl-2-
trifluoromethyloxazolidine (2f). To a solution of the amide 1f (1.770 g, 3.78 mmol, 1.0
equiv) in THF (12 mL) under argon at –78 °C was added a solution of NaHMDS (2.27 mL,
2.0 M in THF, 4.54 mmol, 1.2 equiv). The reaction mixture was stirred at –78 °C for 45 min.
Then NFSI (1.787 g, 5.67 mmol, 1.5 equiv) was added. The reaction mixture was stirred at –
70 °C overnight. The reaction was quenched with a saturated aqueous NH4Cl solution (10
mL). The aqueous layer was extracted three times with ethyl acetate. The organic layers were
combined and dried over MgSO4, filtered and concentrated under reduced pressure. The crude
product (2.329 g) was purified by flash chromatography (cyclohexane/ethyl acetate 98/2 to
95/5) to afford the pure fluorinated product 2f (1.343 g, 2.76 mmol, 73%, > 98% de) as a
white solid. m.p. = 88-90 °C; [α]D –32.5 (c = 1.0, CHCl3); IR 3029, 1679, 1494, 1454, 1379,
1279, 1225, 1179, 1146, 1112, 1077, 1028, 979, 938, 947, 745, 697, 683, 630, 756, 688 cm–1;
1H NMR (400 MHz) (Major conformer) δ 3.00–3.08 (m, 2H), 3.52 (d, 3H, J =13.8 Hz), 3.60
(d, 3H, J = 13.8 Hz), 4.13 (d, 1H, J = 8.5 Hz), 4.37 (m, 1H),4.72 (dd, 1H, J = 8.5, 6.2 Hz),
5.33 (d, 1H, J = 6.2 Hz), 6.21 (q, 1H, JH-F = 5.0 Hz), 7.23–7.50 (m, 15H);.13C NMR (100.5
MHz) (Major conformer) δ 53.9 (d, J = 19.2 Hz), 58.4 (2C), 60.3 (d, J = 7.7 Hz), 76.7, 85.4
(q, J = 33.5 Hz), 89.6 (d, J = 188.8 Hz), 123.4 (q, J = 289.5 Hz), 126.0, 128.3, 128.8, 129.4,
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138.9, 141.1, 169.1 (d, J = 19.2 Hz); F NMR (376.2 MHz) (Major conformer) δ –192.2
(ddd, 1F, J = 49.3, 32.7, 22.6 Hz), –81.0 (bs, 3F, CF3); HRMS (EI+, direct inlet probe) m/z:
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[M+] Calcd for C27H26F4N2O2 486.1930; Found 486.1913; Anal. Calcd for C27H26F4N2O2 C,
66.66; H, 5.39; N, 5.76. Found: C, 66.64; H, 5.19; N, 5.88.
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(R)-2-fluoro-3-phenylpropanoic acid (5c). To a solution of the amide 2c (0.500 g, 1.36
mmol, 1.0 equiv) in diethyl ether (14 mL) cooled at –10 °C and under argon atmosphere, was
slowly added LiAlH4 (0.207 g, 5.44 mmol, 4.0 equiv). The reaction mixture was stirred at –10
°C for 2 h. Water (195 µL, 10.88 mmol, 8 equiv), aqueous NaOH 15% (56 µL, 0.218 mmol,
0.16 equiv) and water (588 µL, 32.64 mmol, 24 equiv) were sequentially added. The resulting
suspension was filtered and the white powder was abundantly washed with diethyl ether. The
filtrate was concentrated under reduced pressure to afford 0.545 g of hemiaminal 3c. The
conversion of the hemiaminal 3c into aldehyde 4c and oxazolidine trans-Fox was completed
by stirring the reaction mixture for 2 h in a slightly acidic chloroform solution (0.08 mmol
acetic acid in 55 mL chloroform). The reaction mixture was then concentrated under reduced
pressure to afford a mixture of aldehyde 4c and chiral auxiliary trans-Fox (0.503 g, quant.).
The NMR spectral data of (R)-2-fluoro-3-phenylpropanal 4c were determined from the crude
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mixture. H NMR (400 MHz) δ 3.06 (ddd, 1H, JH-F = 23.4 Hz, J =15.1, 8.2 Hz), 3.17 (ddd,
1H, JH-F = 30.5 Hz, J = 15.1, 4.1 Hz), 4.95 (ddd, 1H, JH-F = 49.0 Hz, J = 8.2, 4.1 Hz), 7.05–
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7.40 (m, 5H), 9.76 (d, 1H, JH-F = 5.6 Hz); C NMR (100.5 MHz) δ 36.9 (d, J = 20.1 Hz),
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95.2 (d, J = 182.1 Hz), 127.4, 128.8, 129.6, 134.9, 199.9 (d, J = 35.5 Hz); F NMR (376.2
MHz) δ –200.9 (dddd, 1F, J = 49.0, 30.5, 23.5, 5.6 Hz). To a solution of this crude mixture in
t-butanol (20 mL) at room temperature were added a solution of 2-methylbut-2-ene (7.48 mL,
2M in THF, 14.97 mmol, 11.0 equiv) and a solution of NaClO2 (1.231 g, 13.61 mmol, 10
equiv) and NaH2PO4 (1.699 g, 10.89 mmol, 8.0 equiv) in water (12 mL). The resulting yellow
solution was stirred at room temperature overnight. THF and t-butanol were removed under
reduced pressure. Water (25 mL) was added and the aqueous layer was extracted with a
mixture of cyclohexane and ethyl acetate (90/10) (3 x 20 mL). The organic layers were
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combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude
mixture (0.620 g) was purified by silica gel chromatography (DCM/MeOH 98/2 to 96/4) to
give the pure oxazolidine trans-Fox (0.220 g, 1.13 mmol, 74%) as a colorless oil. The
aqueous layer was acidified to pH 2 with an aqueous 1N HCl solution and was then extracted
with ethyl acetate (3 x 25 mL). The acid 5c (0.205 g, 1.226 mmol, 89%) was obtained as a
colorless oil. [α]D +30.4 (c = 1.36, CHCl3); IR 3434, 3030, 2930, 2546, 1730, 1494, 1443,
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1376, 1189, 1076, 933, 857, 795, 742, 695, 647 cm–1; H NMR (400 MHz) δ 3.18 (ddd, 1H,
JH-F = 22.9 Hz, J = 14.9, 7.9 Hz), 3.28 (ddd, 1H, JH-F = 22.9 Hz, J = 14.9, 3.7 Hz), 5.13 (ddd,
1H, JH-F = 48.8 Hz, J = 7.9, 3.7 Hz), 7.25–7.35 (m, 5H), 8.90 (bs, 1H); 13C NMR (100.5 MHz)
δ 38.3 (d, J = 20.1 Hz), 88.7 (d, J = 186.9 Hz), 127.2, 128.5 (2C), 129.3 (2C), 134.9, 173.5 (d,
J = 23.9 Hz); 19F NMR (376.2 MHz) δ –201.0 (dddd, 1F, J = 49.5, 27.0, 24.2, 8.5 Hz);
HRMS (EI+, direct inlet probe) m/z: [M+] Calcd for C9H9FO2 168.0587; Found 168.0595.
(R)-3-dibenzylamino-2-fluoropropanoic acid (5f). The same procedure as used for 4c was
followed starting from a solution of the amide 2f (0.500 g, 1.03 mmol, 1.0 equiv) affording a
mixture of aldehyde 4f and chiral auxiliary trans-Fox (0.502 g, quant.). The NMR spectral
data of (R)-3-dibenzylamino-2-fluoropropanal 4f were determined from the crude mixture. 1H
NMR (400 MHz) δ 2.97 (ddd, 1H, JH-F = 24.2 Hz, J =14.8, 3.3 Hz) 3.04 (ddd, 1H, JH-F = 27.0
Hz, J = 14.8, 6.0 Hz), 3.52 (d, 2H, J = 13.5 Hz), 3.81 (d, 2H, J = 13.5 Hz), 4.90 (ddd, 1H, JH-F
= 46.5 Hz, J = 6.0, 3.3 Hz), 7.12–7.41 (m, 10H), 9.54 (d, 1H, JH-F = 8.5 Hz); 13C NMR (100.5
MHz) δ 52.8 (d, J = 20.1 Hz), 59.1, 95.5 (d, J = 184.0 Hz), 127.4, 128.6, 128.9, 129.0, 129.1,
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130.1, 135.9, 138.6, 198.6 (d, J = 29.7 Hz); F NMR (376.2 MHz) δ –201.0 (dddd, 1F, J =
49.5, 27.0, 24.2, 8.5 Hz). To this crude material was applied the same oxidation protocol as
4c. Purification of the organic layer by silica gel chromatography (DCM/MeOH 98/2 to 96/4)
afforded trans-Fox (0.163 g, 0.75 mmol, 73%) as a colorless oil. The aqueous layer was
acidified to pH 2 with an aqueous 1N HCl solution and was then extracted with ethyl acetate
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(3 x 25 mL). The acid 5f (0.208 g, 0.74 mmol, 71%) was obtained as a colorless oil. [α]D –1.4
(c = 1.6, CHCl3); IR 3028, 2800, 2361, 1737, 1602, 1494, 1453, 1371, 1211, 1135, 1077,
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1027, 974, 908, 729, 696, 646, 619 cm–1; H NMR (400 MHz) δ 3.15 (ddd, 1H, JH-F = 21.1
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Hz, J = 14.3, 3.9 Hz), 3.24 (ddd, 1H, JH-F = 22.7 Hz, J = 14.3, 6.4 Hz), 3.89 (d, 1H, J = 13.5
Hz), 3.99 (d, 1H, J = 13.5 Hz), 5.01 (ddd, 1H, JH-F = 49.5, J = 6.4, 3.9 Hz), 7.21–7.38 (m,
10H), 10.26 (bs, 1H); 13C NMR (100.5 MHz) δ 53.6 (d, J = 22.0 Hz), 58.1, 86.7 (d, J = 185.9
Hz), 128.6, 128.9, 130.0, 134.2, 171.5 (d, J = 21.1 Hz); 19F NMR (376.2 MHz) δ –190.2 (ddd,
1F, J = 49.5, 22.7, 21.1 Hz); HRMS (EI+, direct inlet probe) m/z: [M+] Calcd for
C17H18FNO2 287.1322; Found 287.1322.
(R)-2-fluoro-3-phenylpropan-1-ol (6c). The LiAlH4 reduction of 2c (1.115 g, 3.04 mmol),
followed by a slightly acidic medium hydrolysis gave a mixture of aldehyde 4c and
oxazolidine trans-Fox (1.104 g, 3.04 mmol, 1.0 equiv). To a solution of this crude mixture in
methanol (10.0 mL) was slowly added NaBH4 (0.113 g, 3.04 mmol, 1.0 equiv). The reaction
mixture was stirred at room temperature overnight. The reaction was quenched with water (10
mL). The aqueous layer was extracted with dichloromethane (3 x 15 mL). The organic layers
were combined, dried over MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash chromatography (DCM/MeOH 100/0 to 95/5) afforded the expected
alcohol 6c (0.216 g, 0.79 mmol, 77%) as a colorless oil, and the oxazolidine trans-Fox (0.162
g, 1.05 mmol, 35%) as a colorless oil. [α]D +10.1 (c = 1.8, CHCl3); IR 3348, 3029, 2929,
1604, 1496, 1454, 1355, 1048, 903, 834, 744, 698 cm–1; 1H NMR (400 MHz) δ 2.18 (bs, 1H),
2.92 (ddd, 1H, JH-F = 25.1 Hz, J = 14.2, 6.0 Hz), 3.01 (ddd, 1H, JH-F = 17.2 Hz, J = 14.2, 7.3
Hz), 3.66 (ddd, 1H, JH-F = 25.1 Hz, J = 12.6, 6.0 Hz), 3.75 (ddd, 1H, JH-F = 25.1 Hz, J = 12.6,
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2.8 Hz), 4.76 (ddtd, 1H, JH-F = 48.6 Hz, J = 7.3, 6.0, 2.8 Hz), 7.19–7.33 (m, 5H); C NMR
(100.5 MHz) δ 37.5 (d, J = 22.0 Hz), 64.2 (d, J = 21.1 Hz), 94.8 (d, J = 171.6 Hz), 126.9,
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128.7, 129.4, 136.5; 19F NMR (376.2 MHz) δ –190.7 (dqd, 1F, J = 48.6, 25.1, 17.1 Hz);
HRMS (EI+, direct inlet probe) m/z: [M+] Calcd for C9H11FO 154.0794; Found 154.0789.
(R)-3-dibenzylamino-2-fluoropropan-1-ol (6f). The LiAlH4 reduction of 2f (0.500 g, 1.03
mmol), followed by a slightly acidic medium hydrolysis gave an equimolar mixture of
aldehyde 4f and oxazolidine trans-Fox (0.502 g, 1.03 mmol, 1.0 equiv). To this crude
material was applied the same reduction protocol as 4c. Purification by flash chromatography
(DCM/MeOH 100/0 to 95/5) afforded the expected alcohol 6f (0.216 g, 0.79 mmol, 77%) as a
colorless oil, and the oxazolidine trans-Fox (0.165 g, 0.76 mmol, 74%) as a colorless oil. [α]D
+1.0 (c = 0.8, CHCl3); IR 3368, 3027, 2928, 2805, 1595, 1491, 1448, 1367, 1040, 971, 911,
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838, 739, 694 cm–1; H NMR (400 MHz) δ 2.76 (ddd, 1H, JH-F = 19.0 Hz, J = 14.0, 4.8 Hz),
2.79 (ddd, 1H, JH-F = 16.0 Hz, J = 14.0, 4.8 Hz), 2.99 (bs, 1H), 3.60 (d, 2H, J = 13.4 Hz), 3.66
(ddd, 1H, JH-F = 23.6 Hz, J = 12.4, 4.8 Hz), 3.72 (ddd, 1H, JH-F = 19.9 Hz, J = 12.4, 4.8 Hz),
3.72 (d, 2H, J = 13.4 Hz), 4.63 (dp, 1H, JH-F = 47.8 Hz, J = 4.8 Hz), 7.24–7.37 (m, 10H); 13C
NMR (100.5 MHz) δ 54.3 (d, J = 23.0 Hz), 59.72, 64.32 (d, J = 21.1 Hz), 92.0 (d, J = 171.6
19
Hz), 127.2, 127.5, 128.4, 128.6, 129.2, 138.6, 140.2; F NMR (376.2 MHz) δ –194.38 (m,
1F); HRMS (EI+, direct inlet probe) m/z: [M+] Calcd for C17H20FNO 273.1529; Found
273.1519.
Acknowledgment We thank the French ministry of research for awarding a research
fellowship to H. L. and Central Glass Company for financial support and the gift of
trifluoroacetaldehyde hemiacetal. We also thank the French Fluorine Network.
Supporting Information. General information, NMR spectra of all new compounds and
trans-Fox, (S)-phenetylamide of 5f, (R)-Mosher’s esters of 6c and 6f and chiral HPLC
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chromatogram of the benzylamide of 5c. This material is available free of charge via the
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Internet at http://pubs.acs.org.
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