Stereoselective synthesis of fluorinated isoxazolidines and 2,3- dihydroisoxazoles: A cycloadditive route to enantiomerically pure amino fluoro alcohols

Article abstract of DOI:10.1002/(sici)1099-0690(199907)1999:7<1665::aid-ejoc1665>3.0.co;2-d

3-(Fluoroalkyl)isoxazolidines 6 and -2,3-dihydroisoxazoles 8 have been obtained in enantiomerically pure form with good diastereoselectivity by 1,3- dipolar cycloaddition of diethyl fumarate and dimethylacetylene dicarboxylate, respectively, to the chiral fluorinated nitrone (R)-5. The latter has been prepared from the β-fluoromethyl-β-oxo sulfoxide (R(S)-1, by a synthetic sequence where the chiral and enantiomerically pure sulfinyl function acts as a removable source of chirality. Reductive opening of isoxazolidines 6 then afforded amino fluoromethyl diols 7 in good yields.

Full text of DOI:10.1002/(sici)1099-0690(199907)1999:7<1665::aid-ejoc1665>3.0.co;2-d

FULL PAPER
Stereoselective Synthesis of Fluorinated Isoxazolidines and
2,3-Dihydroisoxazoles: A Cycloadditive Route to Enantiomerically
Pure Amino Fluoro Alcohols
[a]
[b]
[a]
[b]
´
Luca Bruche,* Alberto Arnone, Pierfrancesco Bravo, Walter Panzeri,
Cristina Pesenti,[a] and Fiorenza Viani[b]
Keywords: Fluorine / Cycloadditions / Nitrones / Asymmetric induction / Sulfoxides
3-(Fluoroalkyl)isoxazolidines 6 and -2,3-dihydroisoxazoles 8
have been obtained in enantiomerically pure form with good
diastereoselectivity by 1,3-dipolar cycloaddition of diethyl
fumarate and dimethylacetylene dicarboxylate, respectively,
to the chiral fluorinated nitrone (R)-5. The latter has been
prepared from the β-fluoromethyl-β-oxo sulfoxide (RS)-1, by
a synthetic sequence where the chiral and enantiomerically
pure sulfinyl function acts as a removable source of chirality.
Reductive opening of isoxazolidines 6 then afforded amino
fluoromethyl diols 7 in good yields.
The synthesis of fluoro-substituted heterocycles has re- interesting to consider a chiral and enantiomerically pure
ceived a great deal of attention in recent years, because the fluorinated nitrone as the cycloaddition counterpart, in or-
peculiar biological activity of many of these compounds der to exploit the synthetic potential of its reaction with
makes them effective as antifungal, antiviral, and antitumor dipolarophiles. It must be added that, to the best of our
agents.[1] However, although a great number of achiral knowledge, only an achiral C-trifluoromethyl nitrone has
fluoro heterocycles have been described, only a few enantio- been described in the literature.[7] Whilst a recent paper
merically pure, selectively fluorinated derivatives have been deals with chiral fluoro-substituted nitrones[8] used in inter-
prepared by asymmetric synthesis.[2]
molecular cycloadditions, some examples of such nitrones
One of the most powerful tools for the construction of have been reported in intramolecular applications, but they
five-membered heterocyclic systems with defined substi- have never been isolated.[9] In order to achieve the desired
tution patterns are 1,3-dipolar cycloadditions,[3] owing to synthesis, we decided to use chiral and enantiomerically
their remarkable stereocontrol: One of the key features of pure fluorinated β-oxo sulfoxides[5] as starting materials,
the reaction is the possibility of transferring the stereo- due to their easy availability and great potential.
chemical information present on the dipole or on the di-
polarophile moiety to the newly formed stereocentres of the erically pure β-fluoromethyl nitrone 5, exploiting the sulfi-
heterocyclic ring.[4]
nyl function of the β-oxo sulfoxide 1 as the primary source
We report here the synthesis of the chiral and enantiom-
In the context of an ongoing research program on the of chirality. Also described are its reaction with typical di-
synthesis of optically active fluoroorganic compounds with polarophiles, such as diethyl fumarate and dimethyacetylene
a sulfinyl group acting as a chiral auxiliary,[5] we described dicarboxylate, which allowed the preparation of isoxazolid-
the preparation of some fluoro-substituted 4,5-dihydroisox- ines 6 and 2,3-dihydroisoxazoles 8 with good diastereoselec-
azoles and isoxazolidines. These were obtained by 1,3-di- tivity. Isoxazolidine rings 6 were then reductively opened,
polar cycloaddition of nitrile oxides and nitrones with flu- affording fluoromethyl aminodiols 7.
orinated alkene dipolarophiles bearing a chiral and op-
tically pure sulfinyl group, such as vinyl or allyl sulfoxides.[6]
These heterocycles are also versatile templates in organic
synthesis, since their NϪO bond can be reductively cleaved,
affording open-chain compounds such as β-hydroxy ke-
tones and 1,3-amino alcohols.[4a] In the examples described,
the fluorinated substituent and the sulfinyl chiral auxiliary
both reside on the dipolarophile moiety. Since asymmetric
1,3-dipolar cycloadditions of nitrones can also be efficiently
performed when a chiral substituent is properly sited on
the nitrone,[4e] rather than on the dipolarophile, it appeared
Results and Discussion
β-Fluoromethyl-β-oxo sulfoxide (RS)-1, easily available
through the condensation of the lithium salt of methyl p-
tolyl sulfoxide with ethyl fluoroacetate,[10] was reduced to
the β-hydroxy sulfoxide (2S,RS)-2 with diisobutylaluminium
hydride with high diastereoselectivity[11] (Scheme 1). By
treatment of the latter alcohol with benzyl bromide, the O-
benzyl derivative (2S,RS)-3 was then obtained in good
yield.[12] The sulfinyl function of compound (2S,RS)-3 was
then removed by Pummerer rearrangement[13] performed
with trifluoroacetic anhydride and HgCl2,[14] to give the al-
dehyde (R)-4, that was not isolated. By direct treatment[9]
of the crude mixture with N-benzylhydroxylamine hydro-
chloride, the stable, chiral and enantiomerically pure (vide
[a]
Dipartimento di Chimica del Politecnico,
Via Mancinelli 7, I-20131 Milano, Italy
[b]
C.N.R. Ϫ Centro di Studio sulle Sostanze Organiche Naturali,
Via Mancinelli 7, I-20131 Milano, Italy
Fax: (internat.) ϩ 39-02/2399-3080
E-mail: bruche@dept.chem.polimi.it
Eur. J. Org. Chem. 1999, 1665Ϫ1670
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0707Ϫ1665 $ 17.50ϩ.50/0
1665

´
L. Bruche, A. Arnone, P. Bravo, W. Panzeri, C. Pesenti, F. Viani
FULL PAPER
infra) nitrone (R)-5 was obtained in 70% yield. The (Z) configuration of 4-H with respect to 5-H, and therefore also
form was assigned to the nitrone, on the basis of NOE (3%) with 3-H, follows from the stereoconservative mechanism of
observed between the benzylic hydrogen atoms at a chemi- 1,3-dipolar cycloadditions,[3] being trans-configured in the
cal shift of δ ϭ 4.86 and the olefinic hydrogen at δ ϭ 6.71.[8] starting olefin, diethyl fumarate. In the major isomer,
(3R,4S,5S,1ЈR)-6, the C-3 side chain assumes the preferred
configuration shown in Figure 1, as evidenced by the NOEs
observed between 1Ј-H and the N-CH2 protons, between
the fluorine atom and 3-H but not with 4-H, and the
smaller enhancements observed for the CH2F protons with
respect to the OCH2 ones by irradiation of 4-H. All these
findings require that the chirality of C-3, C-4, and C-5 is
(R,S,S), respectively, being (R) the absolute configuration
of C-1Ј. In the minor isomer (3S,4R,5R,1ЈR)-6, the smaller
NOEs observed for the OCH2 protons with respect to the
CH2F ones by irradiation of 4-H, together with the lack of
sizable NOEs between 1Ј-H and the N-CH2 protons, and
the enhancements of both 3-H and 4-H by irradiation of the
fluorine atom indicate that the C-3 side chain preferentially
adopts the conformation depicted in Figure 1, thus con-
firming that the ring carbon atoms have opposite chirality.
It must be noted that a progressive addition of the optically
Scheme 1. Synthesis of nitrone (R)-5 from β-fluoromethyl-β-oxo
active shift reagent Eu(TFC)3, {tris[3-(heptafluoropro-
pylhydroxymethylene)-(ϩ)-camphorate]europium(III)}, to a
CDCl3 solution of major-6 showed no doubling of 1H-
NMR signals. This fact showed the enantiomeric purity of
compound major-6 to be Ն 95% and therefore also demon-
strated the enantiomeric purity of its precursor nitrone
(R)-5.
sulfoxide (Rs)-1
Nitrone (R)-5 was then treated with two typical sym-
metrical dipolarophiles. The reaction of the nitrone with a
3:1 molar ratio of diethyl fumarate was performed in CCl4;
after 7 h stirring at room temperature, the two diastereoiso-
meric isoxazolidines (3R,4S,5S,1ЈR)-6 (major) and
(3S,4R,5R,1ЈR)-6 (minor) were isolated in a 5.5:1 ratio from
the crude reaction mixture by flash column cromatography,
in 72% overall yield (Scheme 2).
Figure 1. Selected NOEs in isoxazolidines 6
From the mechanistic point of view, both isoxazolidines
6 result from a 100% endo attack of the alkene dipolaro-
phile on the (Z)-nitrone 5 (Scheme 3): Such total endo selec-
tivity may be ascribed to the steric interaction in the tran-
sition state between one of the ethoxy groups of diethyl fu-
marate and the bulky C substituent of the nitrone, that
leads them in an anti relationship in the cycloadducts. The
facial diastereoselectivity shown in the cycloaddition in fa-
vour of the major isomer (3R,4S,5S,1ЈR)-6 could be ex-
Scheme 2. 1,3-Dipolar cycloaddition of nitrone (R)-5 with diethyl
fumarate
The structure and the absolute stereochemistry of com- plained by comparison between the two preferred confor-
1
pounds 6 were determined by analysis of their H-, 13C-, mations of the nitrone in the transition state. These confor-
and 19F-NMR spectra and NOE experiments (see Exper- mations can reasonably be assumed to be the same as those
imental section and Figure 1) and by chemical evidence. proposed by DeShong for structurally related nitrones,[15]
In both the diastereoisomeric compounds, (3R,4S,5S,1ЈR)- referring to Felkin-Ahn models[16] (Scheme 4). As sug-
6 and (3S,4R,5R,1ЈR)-6, mutual NOEs were observed be- gested by Ahn, the polarized carbonϪoxygen bond is or-
tween 3-H and 5-H, which must therefore be disposed on thogonal to the plane of the nitrone, thus excluding any
the same side of the ring in the two molecules. The anti conformation where the C substituent is perpendicular to
1666
Eur. J. Org. Chem. 1999, 1665Ϫ1670

A Cycloadditive Route to Enantiomerically Pure Amino Fluoro Alcohols
FULL PAPER
the double bond. The attack of the dipolarophile takes
place preferably onto conformation A, which is expected to
be the more reactive conformer, since the approach of the
dipolarophile to the nitrone carbon atom avoids interac-
tions with the bulky C substituent, thus leading to the
major cycloadduct (3R,4S,5S,1ЈR)-6.
Scheme 5. Catalytic hydrogenation of isoxazolidines 6
mixture by flash column cromatography, in 76% overall
yield (Scheme 6). The stereochemistry of the two 2,3-di-
hydroisoxazoles 8 was tentatively assigned on the basis of
chemical-shift criteria, since no significant NOE enhance-
ments were observed. In fact, in the major isomer the CH2F
protons resonate at a lower field with respect to the corre-
sponding protons of the minor isomer and the OCH2 pro-
tons at a higher field. This behaviour may be attributed to
the shielding effect exerted by the C-4ϪC-5 double bond,
in the hypothesis that in 2,3-dihydroisoxazoles 8 the C-3
side chain assumes the same preferred conformation
adopted in the corresponding isoxazolidines 6. Further-
more, such stereochemistry should also follow from the ob-
served general behaviour of the same nitrone with structur-
ally related ethylene and acetylene dipolarophiles.[3][4] The
lower reactivity of dimethylacetylene dicarboxylate with re-
spect to diethyl fumarate reflects the general behaviour with
nitrones of acetylenic dipolarophiles, compared to ethyl-
enic ones.[4a]
Scheme 3. Proposed model for the total endo selectivity of the cy-
cloaddition
Scheme 4. Preferred conformations of the nitrone (R)-5 in the tran-
sition state
In order to obtain open-chain compounds, the 5.5:1 mix-
ture of isoxazolidines 6 was subsequently hydrogenated in
ethyl acetate at atmospheric pressure in the presence of
Pd(OH)2:[17] After 30 min of stirring at 50°C, the two dia-
stereoisomeric amino diols (2S,3S,4R,5R)-7 (major) and
(2R,3R,4S,5R)-7 (minor) were isolated in a 5:1 ratio by
flash column cromatography in 58% overall yield (Scheme
5). As evidenced by spectral and analytical data (see Exper-
imental Section), the reductive cleavage of the NϪO bond
was accompanied by a concomitant complete debenzy-
lation, thus allowing the deprotection of both the amino
and the hydroxy functions.
The reaction of nitrone (R)-5 with a 20% molar excess of
dimethylacetylene dicarboxylate was performed in CCl4 at
40°C: After stirring for 6 h, the two diastereoisomeric 2,3-
dihydroisoxazoles (3R,1ЈR)-8 (major) and (3S,1ЈR)-8
Scheme 6. 1,3-Dipolar cycloaddition of nitrone (R)-5 with dimethy-
(minor) were isolated in a 2:1 ratio from the crude reaction lacetylene dicarboxylate
Eur. J. Org. Chem. 1999, 1665Ϫ1670
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´
L. Bruche, A. Arnone, P. Bravo, W. Panzeri, C. Pesenti, F. Viani
FULL PAPER
5.22 (d, J ϭ 3.1 Hz, 2 H, CϭCH2), 7.1Ϫ7.4 (m, 5 H, ArH), 9.27
(s, 1 H, CHO). Ϫ MS (EI); m/z (%): 162 (8) [M ϩ H]ϩ, 133 (23)
[C9H9O]ϩ·, 107 (8) [C7H7O]ϩ·, 105 (10) [C7H5O]ϩ·, 91 (100)
[C7H7]ϩ·. Ϫ IR (film): ν˜ ϭ 3034 cmϪ1 (νCHArom), 2927 (νCH2), 2854,
1705 (νCHO), 1613, 1456, 1311, 1261 (νCϭC), 1047, 872, 741, 698.
Ϫ The crude intermediate aldehyde 4 (296 mg, 1.6 mmol) was sus-
pended in methanol (10 mL) and the resulting slurry was added
dropwise to a suspension of N-benzylhydroxylamine hydrochloride
(0.808 g, 5.1 mmol), sodium carbonate (0.537 g, 5.1 mmol) and cal-
cium chloride (0.562 g, 5.1 mmol) in methanol (4.5 mL). The mix-
ture was stirred at room temp. for 2 h. The solvent was removed
under reduced pressure and the residue was purified by flash chro-
matography (n-hexane/ethyl acetate from 3:2 to 1:1) to give 320 mg
Conclusion
In conclusion, an efficient general route to chiral fluori-
nated nitrones has been described: Starting from properly
fluoro-substituted β-oxo sulfoxides and different N-alkylhy-
droxylamines, a wide variety of such nitrones can be pre-
pared. On considering the great deal of unsaturated mol-
ecules that can be used as dipolarophiles, there is clear evi-
dence that the described method is a valid and effective
route to a wide variety of chiral, selectively fluorinated isox-
azolidine and 2,3-dihydroisoxazole systems of potential bio-
logical interest. The reductive opening of the obtained het-
erocycles can then efficiently allow the preparation of highly
functionalized and enantiomerically pure fluorinated
amino alcohols.
20
of (R)-5: Yield 70%, m.p. 63°C. Ϫ Rf ϭ 0.33. Ϫ [α]D ϭ ϩ21.5
1
(c ϭ 1.2, CHCl3). Ϫ H NMR (CDCl3) δ ϭ 4.56 and 4.62 (br. d,
J ϭ 12.0 Hz, 2 H, OCH2), 4.61 (ddd, J ϭ 47.5, 9.7 and 4.1 Hz, 1H,
CHaF), 4.65 (ddd, J ϭ 47.5, 9.7 and 2.8 Hz, 1 H, CHbF), 4.86 (br.
s, 2 H, NCH2), 4.92 (dddd, J ϭ 24.5, 5.9, 4.1 and 2.8 Hz, 1H,
OCH), 6.71 (br. d, J ϭ 5.9 Hz, 1 H, NϭCH), 7.2Ϫ7.5 (m, 10 H,
ArH). Ϫ 13C NMR (CDCl3), δ ϭ 69.49 (T, NCH2); 72.49 (T,
Experimental Section
2
1
OCH2); 73.69 (Dd, JC,F ϭ 20.4 Hz, OCH); 81.44 (Td, JC,F
ϭ
General: Melting points (m.p.) are uncorrected and obtained with
a capillary apparatus. Ϫ Polarimetric analyses were performed with
JASCO IP-181 and PROPOL polarimeters. Ϫ Analytical thin-layer
chromatography (TLC) were routinely used to monitor reactions.
Plates precoated with E. Merck silica gel 60 F254 of 0.25 mm thick-
ness were used. Flash chromatographies (FC) were performed with
173.9 Hz, CH2F); 127.73 (D), 127.84 (D), 128.31 (D), 128.84 (D),
128.99 (D), 129.11 (D), 132.02 (S) and 137.15 (S); 135.60 (Sd,
3JC,F ϭ 8.0 Hz, NϭCH). Ϫ 19F NMR (CDCl3) δ ϭ Ϫ230.65 (br.
dt, J ϭ 24.5 and 47.5 Hz, 1 F, CH2F). Ϫ Selected NOE: {NϭCH}
enhanced NCH2 (3%). Ϫ IR (KBr) ν˜ ϭ 3031 cmϪ1, 2959, 1600
(νCϭN), 1455, 1169 (νNϪO), 1027, 749, 700. Ϫ MS (EI); m/z (%):
silica gel 60 (230Ϫ400 ASTM mesh). Ϫ H-, 13C-, and 19F-NMR
1
288 (8) [M ϩ H]ϩ, 181 (21) [C10H12FNO]ϩ·, 161 (7) [C10H11NO]ϩ·
,
spectra were recorded with a Bruker AC 250L spectrometer, op-
erating at 250.13, 62.89 and 235.35 MHz, respectively, in CDCl3
solutions. Chemical shifts are expressed in ppm (δ), using tetra-
123 (6) [C7H9NO]ϩ·, 105 (3) [C7H7N]ϩ·, 91 (100) [C7H7]ϩ·, 77 (8)
[C6H5]ϩ·. Ϫ C17H18FNO2 (287.33): calcd. C 71.06, H 6.31, N 4.87;
found C 70.95, H 6.40, N 4.76.
methylsilane (TMS) as internal standard for H and 13C nuclei (δH
1
and δC ϭ 0.00), whilst C6F6 was used as external standard (δF
ϭ
Reaction of Nitrone (R)-5 with Diethyl Fumarate: Neat diethyl fum-
arate (69 µL, 0.4 mmol) was added by syringe to a solution of
nitrone (R)-5 (100 mg, 0.3 mmol) in CCl4 (7 mL) kept under nitro-
gen. The reaction mixture was stirred at room temperature for
3.5 h. Then a furher excess of diethyl fumarate (83 µL, 0.48 mmol)
was added and the reaction was stirred for additional 3.5 h. The
solvent was evaporated to dryness and 19F- and 1H-NMR analyses
of the crude reaction mixture revealed a 5.5:1 mixture of isoxazolid-
ines (3R,4S,5S,1ЈR)-/(3S,4R,5R,1ЈR)-6. The residue was purified by
flash chromatography with an n-hexane/ethyl acetate (9:1) mixture
as eluant to give 104 mg of compounds 6 as the only detectable
epimeric mixture of compounds (72% overall yield, Rf ϭ 0.35).
Further flash purifications with a cyclohexane/ethyl acetate (9:1)
mixture as eluant afforded the isolation of the two diastereoiso-
meric isoxazolidines 6 in enantiomerically and diastereomerically
pure form.
Ϫ162.90) for 19F. Coupling constants are expressed in Hertz (Hz).
In the 13C-NMR signal assignment, capital letters refer to the pat-
tern resulting from directly bonded (C,H) couplings and lower case
letters to the one from (C,F) couplings. Ϫ Mass spectra were regis-
tered on a TSQ 70 Finnigan Mat three-stage quadrupole instru-
ment. DIS (Direct Inlet System) was used for pure compounds. Ϫ
Infrared spectra were performed using a PerkinϪElmer System
2000 FT-IR (scan range: 15600 cmϪ1; combined scan direction).
Ϫ Commercially available reagent-grade solvents were employed
without purification. All reactions where anhydrous organic sol-
vents were employed were performed under nitrogen, after flame-
drying procedures of the glass apparatus. Compounds 1[10], 2[11]
and 3[12] were prepared as described previously.
,
Synthesis of the Fluorinated Nitrone (R)-5: A solution of trifluoro-
acetic anhydride (0.39 mL, 1.96 mmol) in CH3CN was added drop-
wise to a solution of the O-benzyl derivative (2S,RS)-3 (300 mg,
20
(3R,4S,5S,1ЈR)-6 (Major): Rf ϭ 0.37. Ϫ [α]D ϭ ϩ19.4 (c ϭ 0.6,
1
0.98 mmol) and sym-collidine (0.29 mL, 2.16 mmol) in CH3CN (3 CHCl3). Ϫ H NMR (CDCl3): δ ϭ 1.27 and 1.31 (t, J ϭ 7.1 Hz, 6
mL), cooled at Ϫ25°C and stirred under nitrogen. The mixture was
H, 2 OCH2Me), 3.58 (dd, J ϭ 6.6 and 4.3 Hz, 1 H, 3-H), 3.71
allowed to reach room temperature and, after total consumption (dddd, J ϭ 20.1, 6.6, 5.6, and 3.0 Hz, 1 H, 1Ј-H), 3.86 (dd, J ϭ 5.7
of the substrate, it was cooled again at Ϫ10°C; solid K2CO3 was and 4.3 Hz, 1 H, 4-H), 4.07 and 4.10 (br. d, J ϭ 13.5 Hz, 2 H,
then added until pH ϭ 7, then a solution of of HgCl2 (800 mg,
2.94 mmol) in CH3CN (4 mL) was added portionwise. A white pre-
NCH2), 4.1Ϫ4.3 (m, 4 H, 2 OCH2Me), 4.39 (ddd, J ϭ 47.5, 10.1,
and 5.6 Hz, 1 H, CHaF), 4.59 (ddd, J ϭ 47.2, 10.1, and 3.0 Hz, 1
cipitate formed slowly. The reaction mixture was allowed to reach H, CHbF), 4.61 and 4.71 (br. d, J ϭ 11.6 Hz, 2 H, OCH2), 5.05 (d,
room temperature, and stirring was continued for 2.5 h. The white
solid was filtered through a Celite pad, and the filtrate was concen-
trated to dryness under reduced pressure. An attempt to isolate the
intermediate aldehyde 4 as a pure compound was performed
through purification of the crude reaction mixture by flash chroma-
tography with an n-hexane/ethyl acetate (8:2) mixture as eluant.
Only 2-benzyloxyprop-2-enal[18] was recovered in 55% yield: Rf ϭ
J ϭ 5.7 Hz, 1 H, 5-H), 7.2Ϫ7.5 (m, 10 H, ArH). Ϫ 13C NMR
(CDCl3): δ ϭ 14.09 and 14.21 (Q, 2 OCH2Me); 53.90 (D, C-4);
60.59 (T, NCH2); 61.78 and 61.86 (T, 2 OCH2Me); 68.59 (Dd,
3JC,F ϭ 7.2 Hz, C-3); 73.00 (T, OCH2); 77.52 (Dd, 2JC,F ϭ 18.5 Hz,
C-1Ј); 78.55 (D, C-5); 83.16 (Td, JC,F ϭ 171.5 Hz, CH2F); 127.53
(D), 127.65 (D), 127.68 (D), 128.26 (D), 128.34 (D), 128.92 (D),
136.28 (S) and 137.89 (S) (ArC); 169.75 and 171.90 (S, 2 CO2Et).
1
0.40.Ϫ H NMR (CDCl3): δ ϭ 4.88 (br. s, 2 H, OCH2), 5.10 and
Ϫ
19F NMR (CDCl3): δ ϭ Ϫ231.40 (br. ddd, J ϭ 47.5, 47.2, and
1668
Eur. J. Org. Chem. 1999, 1665Ϫ1670

A Cycloadditive Route to Enantiomerically Pure Amino Fluoro Alcohols
20.1 Hz, 1 F, CH2F). Ϫ Selected NOEs (CDCl3): {3-H} enhanced (Q, 2 Me), 47.83 (D, C-3), 57.07 (Dd, JC,F ϭ 5.5 Hz, C-4), 62.10
FULL PAPER
3
2
4-H (2%), 5-H (1%), 2-CH2 (2%), 1Ј-OCH2 (0.5%) and 1Ј-CH2 (T, 2 OCH2), 70.90 (D, C-2), 71.76 (Dd, JC,F ϭ 19.0 Hz, C-5),
(1%); {4-H} enhanced 3-H (2%), 5-H (2.5%), 1Ј-H (2.5%), 1Ј-OCH2 85.44 (Td, 1JC,F ϭ 170.0 Hz, C-6), 172.11 and 177.52 (S, 2 CO). Ϫ
(1%) and 1Ј-CH2 (0.5%); {5-H} enhanced 3-H (0.5%), 4-H (2%), 19F NMR (CD3OD): δ ϭ Ϫ230.75 (dt, J ϭ 21.5 and 47.3 Hz,
and 2-CH2 (1.5%); {1Ј-H} enhanced 4-H (3%), 2-CH2 (0.5%), 1Ј-
CH2F). Ϫ IR (KBr): ν˜ ϭ 3451 cmϪ1, 3341 (νOH, νNH), 1708 (νCOO).
OCH2 (2%) and 1Ј-CH2 (1%); {2-CH2} enhanced 3-H (10.5%), 5- Ϫ MS (FAB/Xe); m/z (%): 282 (25) [M ϩ H]ϩ, 244 (20)
H (9%) and 1Ј-H (2%); {1Ј-OCH2} enhanced 3-H (0.5%), 4-H [C11H18NO5]ϩ, 236 (85) [C9H15FNO5]ϩ, 218 (63) [C9H13FNO4]ϩ,
(0.5%) and 1Ј-H (2%); {F} enhanced 3-H (1.5%), 1Ј-H (2.5%), 1Ј-
190 (45) [C8H12O5]ϩ·, 172 (78) [C7H12O4]ϩ·, 91 (100) [C3H6FNO]ϩ·
Ϫ C11H20FNO6 (281.28): calcd. C 46.97, H 7.17, N 4.98; found C
.
OCH2 (0.5%) and 1Ј-CH2 (7.5%). Ϫ IR (film): ν˜ ϭ 2984 cmϪ1
,
1735, 1455, 1372, 1218, 1097, 1030, 754, 699. Ϫ MS (EI): 460 (5) 46.84, H 7.06, N 5.07.
[M ϩ H]ϩ, 386 (1) [C22H25FNO4]ϩ, 307 (7) [C16H21NO5]ϩ·, 306
(2R,3R,4S,5R)-7 (Minor): [α]D20 ϭ ϩ25.6 (c ϭ 0.1, CH3OH). Ϫ 1H
(40) [C16H20NO5]ϩ, 280 (10) [C14H15FNO4]ϩ, 260 (37)
[C11H15FNO5]ϩ, 164 (10) [C9H7FNO]ϩ, 91 (100) [C7H7]ϩ·. Ϫ
C25H30FNO6 (459.51): calcd. C 65.35, H 6.58, N 3.05; found C
65.47, H 6.50, N 3.13.
NMR (CD3OD ϩ D2O): δ ϭ 1.28 (t, J ϭ 7.2 Hz, 6 H, 2 Me), 3.39
(dd, J ϭ 8.3 and 3.9 Hz, 1 H, 3-H), 3.79 (ddt, J ϭ 15.3, 3.6, and
5.8 Hz, 1 H, 5-H), 4.01 (dd, J ϭ 3.9 and 3.6 Hz, 1 H, 4-H), 4.17
and 4.18 (q, J ϭ 7.2 Hz, 4 H, 2 CH2), 4.38 (dd, J ϭ 47.1 and
5.8 Hz, 2 H, CH2F), 4.54 (d, J ϭ 8.3 Hz, 1 H, 2-H). Ϫ 13C NMR
(CD3OD): δ ϭ 14.53 (Q, 2 Me), 50.18 (D, C-3), 56.97 (Dd, 3JC,F ϭ
5.5 Hz, C-H), 62.11 (T, 2 OCH2), 70.87 (D, C-2), 71.85 (Dd,
(3S,4R,5R,1ЈR)-6 (Minor): Rf ϭ 0.33. Ϫ 1H NMR (CDCl3/[D6]ben-
zene, 1:2): δ ϭ 1.28 (t, J ϭ 7.1 Hz, 6 H, 2 OCH2Me), 3.66 (dddd,
J ϭ 20.2, 6.7, 5.4, and 3.6 Hz, 1 H, 1Ј-H), 3.68 (ddd, J ϭ 6.7, 4.7,
and 1.2 Hz, 1 H, 3-H), 3.77 (dd, J ϭ 5.7 and 4.7 Hz, 1 H, 4-H),
4.12 and 4.15 (br. d, J ϭ 13.5 Hz, 2 H, NCH2), 4.21 and 4.23 (q,
J ϭ 7.1 Hz, 4 H, 2 OCH2Me), 4.55 (ddd, J ϭ 47.1, 10.5, and
5.4 Hz, 1 H, CHaF), 4.56 (ddd, J ϭ 47.3, 10.5, and 3.6 Hz, 1 H,
CHbF), 4.60 and 4.63 (br. d, J ϭ 11.7 Hz, 2 H, OCH2), 4.99 (d,
J ϭ 5.7 Hz, 1 H, 5-H), 7.2Ϫ7.4 (m, 10 H, ArH). Ϫ 13C NMR
(CDCl3) δ ϭ 14.09 and 14.21 (Q, 2 OCH2Me); 53.18 (D, C-4);
61.30 (T, NCH2), 61.78 and 61.86 (T, 2 OCH2Me); 68.19 (Dd,
3JC,F ϭ 6.9 Hz, C-3); 72.95 (T, OCH2); 78.29 (Dd, 2JC,F ϭ 18.5 Hz,
1
2JC,F ϭ 19.8 Hz, C-5), 85.16 (Td, JC,F ϭ 170.6 Hz, C-6), 171.93
and 177.90 (S, 2 CO). Ϫ 19F NMR (CD3OD) δ ϭ Ϫ227.68 (dt,
J ϭ 15.3 and 47.1 Hz, CH2F). Ϫ MS (FAB/Xe); m/z (%): 282 (55)
[M ϩ H]ϩ, 244 (48) [C11H18NO5]ϩ, 236 (82) [C9H15FNO5]ϩ, 198
(42) [C9H12NO4]ϩ, 190 (45) [C8H12O5]ϩ·, 170 (100) [C7H10O4]ϩ·, 91
(78) [C3H6FNO]ϩ·. Ϫ C11H20FNO6 (281.20): calcd. C 46.97, H
7.17, N 4.98; found C 47.09, H 7.08, N 4.86.
Reaction of Nitrone (R)-5 with Dimethylacetylene Dicarboxylate:
Neat dimethylacetylene dicarboxylate (61 µL, 0.5 mmol) was added
by syringe to a solution of nitrone (R)-5 (120 mg, 0.4 mmol) in
CCl4 (8.5 mL) under nitrogen. The reaction mixture was stirred at
40°C for 6 h. The solvent was evaporated to dryness and the resi-
due was purified by flash chromatography with an n-hexane/ethyl
acetate (4:1) mixture as eluant to give 2,3-dihydroisoxazoles (3R/
S,1ЈR)-8 as the only detectable 2:1 epimeric mixture of compounds:
129 mg (76% yield); Rf ϭ 0.35.
1
C-1Ј); 78.70 (D, C-5); 83.53 (Td, JC,F ϭ 171.0 Hz, CH2F); 127.45
(D), 127.67 (D), 127.83 (D), 128.26 (D), 128.34 (D), 128.84 (D),
136.48 (S), and 137.73 (S) (ArC); 169.43 and 171.80 (S, 2 CO2Et).
Ϫ
19F NMR (CDCl3): δ ϭ Ϫ230.45 (br. ddd, J ϭ 47.3, 47.1, and
20.2 Hz, 1 F, CH2F). Ϫ Selected NOEs (CDCl3/[D6]benzene, 1:2):
{3-H} enhanced 4-H (1%), 5-H (1%), 1Ј-H (2%), 2-CH2 (2%), 1Ј-
OCH2 (1%) and 1Ј-CH2 (1%); {4-H} enhanced 3-H (1%), 5-H (2%),
1Ј-H (3%), 1Ј-OCH2 (0.5%) and 1Ј-CH2 (1.5%); {5-H} enhanced
3-H (1%), 4-H (2.5%) and 2-CH2 (1.5%); {1Ј-H} enhanced 3-H
(1%), 4-H (2.5%), 1Ј-OCH2 (2%) and 1Ј-CH2 (1.5%); {2-CH2} en-
hanced 3-H (11%) and 5-H (11.5%); {1Ј-OCH2} enhanced 3-H
(2%) and 1Ј-H(3%); {1Ј-CH2} enhanced 4-H (3.5%) and 1Ј-H (3%);
{F} enhanced 3-H (3%), 4-H (3.5%), 1Ј-H (6%), 1Ј-OCH2 (1.5%)
and 1Ј-CH2 (10.5%). Ϫ IR (film): ν˜ ϭ 2928.21 cmϪ1, 2365, 1734
(νCOO), 1456, 1374, 1265, 1218, 1098, 1029, 757. Ϫ MS (EI); m/z
(%): 460 (5) [M ϩ H]ϩ, 386 (20) [C22H25FNO4]ϩ, 306 (20)
[C16H20NO5]ϩ, 280 (5) [C14H15FNO4]ϩ, 260 (20) [C11H15FNO5]ϩ,
165 (8) [C9H8FNO]ϩ·, 91 (100) [C7H7]ϩ·. Ϫ C25H30FNO6 (459.51):
calcd. C 65.35, H 6.58, N 3.05; found C 65.27, H 6.66, N 3.15.
1
(3R,1ЈR)-8 (Major): H NMR (CDCl3): δ ϭ 3.64 and 3.88 (s, 6 H,
2 OMe), 3.85 (ddt, J ϭ 19.0, 4.8, and 4.5 Hz, 1 H, 1Ј-H), 3.94 and
4.27 (br. d, J ϭ 12.9 Hz, 2 H, NCH2), 4.47 (dd, J ϭ 4.8 and 1.3 Hz,
1 H, 3-H), 4.48 and 4.61 (br. d, J ϭ 11.7 Hz, 2 H, OCH2), 4.55
(dd, J ϭ 47.5 and 4.5 Hz, 2 H, CH2F), 7.1Ϫ7.5 (m, 10 H, ArH).
Ϫ
13C NMR (CDCl3): δ ϭ 51.96 and 53.23 (Q, 2 OMe); 63.58 (T,
3
NCH2); 69.29 (Dd, JC,F ϭ 9.2 Hz, C-3); 72.66 (T, OCH2); 79.16
2
1
(Dd, JC,F ϭ 18.5 Hz, C-1Ј); 82.92 (Td, JC,F ϭ 170.2 Hz, CH2F);
106.95 (S, C-4); 127.86 (D), 128.27 (D), 128.39 (D), 128.46 (D),
128.60 (D), 129.63 (D), 134.33 (S) and 137.74 (S) (ArC); 152.02 (S,
C-5); 159.06 and 162.62 (S, 2 CO2Me). Ϫ 19F NMR (CDCl3): δ ϭ
Ϫ231.35 (br. dt, J ϭ 19.0 and 47.5 Hz, 1 F, CH2F). Ϫ MS (EI);
m/z (%): 430 (1) [M ϩ H]ϩ, 410 (2) [C23H24NO6]ϩ, 409 (4)
Catalytic Hydrogenation of Isoxazolidines 6: A solution of the 5.5:1
mixture of isoxazolidines 6 (95 mg, 0.21 mmol) in ethyl acetate (8
mL) was hydrogenated at atmospheric pressure and at 50°C for
30 min in the presence of 20% Pd(OH)2/C (30 mg). The catalyst
was removed by filtration through a Celite pad, and the solvent
was removed under reduced pressure. The residue was flash-chro-
matographed on a silica gel column with a toluene/EtOH (4:1) mix-
ture as eluant, affording amino diols 7 (58% yield).
[C23H23NO6]ϩ·, 370 (1) [C21H21FNO4]ϩ, 353 (4) [C17H20FNO6]ϩ·
276 (8) [C14H14NO5]ϩ, 218 (5) [C12H12NO3]ϩ, 185 (18)
[C7H7NO5]ϩ· 156 (6) [C5H2NO5]ϩ, 91 (100) [C7H7]ϩ·
. Ϫ
,
,
C23H24FNO6 (429.45): calcd. C 64.33, H 5.63, N 3.26; found C
64.43, H 5.55, N 3.18.
1
(3S,1ЈR)-8 (Minor): H NMR (CDCl3): δ ϭ 3.62 and 3.91 (s, 6 H,
2 OMe), 3.88 and 4.32 (br. d, J ϭ 12.6 Hz, 2 H, NCH2), 3.90 (dddd,
J ϭ 12.0, 6.5, 5.5, and 2.5 Hz, 1 H, 1Ј-H), 4.12 (ddd, J ϭ 46.7, 9.6,
20
(2S,3S,4R,5R)-7 (Major): [α]D ϭ Ϫ54.3 (c ϭ 0.2, CH3OH). Ϫ
M.p. 112Ϫ113°C (CHCl3/AcOEt, 9:1). Ϫ 1H NMR (CD3OD ϩ and 5.5 Hz, 1 H, CHaF), 4.30 (br. d, J ϭ 2.5 Hz, 1 H, 3-H), 4.39
D2O): δ ϭ 1.27 (t, J ϭ 7.2 Hz, 6 H, 2 Me), 3.50 (dd, J ϭ 8.6 and
3.7 Hz, 1 H, 3-H), 3.78 (dddd, J ϭ 21.5, 5.1, 4.4, and 4.1 Hz, 1 H, J ϭ 11.9 Hz, 2 H, OCH2), 7.1Ϫ7.5 (m, 10 H, ArH). Ϫ 13C NMR
5-H), 3.99 (dd, J ϭ 4.4 and 3.7 Hz, 1 H, 4-H), 4.17 and 4.18 (q, (CDCl3): δ ϭ 51.64 and 52.93 (Q, 2 OMe); 63.66 (T, NCH2); 68.72
J ϭ 7.2 Hz, 4 H, 2 OCH2), 4.39 (ddd, J ϭ 47.3, 10.0, and 4.1 Hz, (Dd, JC,F ϭ 7.5 Hz, C-3); 73.60 (T, OCH2); 75.66 (Dd, JC,F
(ddd, J ϭ 47.2, 9.6, and 6.5 Hz, 1 H, CHbF), 4.53 and 4.66 (br. d,
3
2
ϭ
1
1 H, CHHF), 4.41 (ddd, J ϭ 47.3, 10.0, and 5.1 Hz, 1 H, CHHF), 18.5 Hz, C-1Ј); 82.92 (Td, JC,F ϭ 170.2 Hz, CH2F); 104.22 (S, C-
4.52 (d, J ϭ 8.6 Hz, 1 H, 2-H). Ϫ 13C NMR (CD3OD) δ ϭ 14.53 4); 127.72 (D), 128.27 (D), 128.39 (D), 128.48 (D), 128.60 (D),
Eur. J. Org. Chem. 1999, 1665Ϫ1670
1669

´
L. Bruche, A. Arnone, P. Bravo, W. Panzeri, C. Pesenti, F. Viani
FULL PAPER
Merli, Tetrahedron: Asymmetry 1993, 4, 2131; P. Bravo, L. Bru-
130.01 (D), 134.01 (S), and 137.65 (S) (ArC); 153.77 (S, C-5);
159.33 and 162.41 (S, 2 CO2Me). Ϫ 19F NMR (CDCl3): δ ϭ
Ϫ229.51 (br. ddd, J ϭ 47.2, 46.7, and 12.0 Hz, 1 F, CH2F).
´
che, G. Fronza, A. Merli, Gazz. Chim. Ital. 1994, 124, 275; A.
´
Arnone, P. Bravo, L. Bruche, P. Seresini, J. Chem. Res. 1996,
´
(S) 198; A. Arnone, P. Bandiera, P. Bravo, L. Bruche, M.
´
Zanda, Gazz. Chim. Ital. 1996, 126, 773; P. Bravo, L. Bruche,
P. Seresini, M. Zanda, A. Arnone J. Heterocycl. Chem. 1997,
[1]
M. J. Silvester, Aldrichim. Acta 1991, 24, 31; Biomedical Aspects
´
34, 489; A. Arnone, P. Bandiera, P. Bravo, L. Bruche, M.
of Fluorine Chemistry (Ed.: R. Filler, A. Kobayashi), Elsevier,
New York, 1992; M. J. Silvester, Adv. Heterocycl. Chem. 1994,
59, 1; K. Burger, U. Wucherpfennig, E. Brunner, Adv. Hetero-
cycl. Chem. 1994, 60, 1; Fluoroorganic Chemistry: Synthetic
Challenges and Biomedical Rewards (Ed.: G. Resnati, V. A. Solo-
shonok), Tetrahedron Symposium-in-Print No. 58, Tetrahedron
1996, 52, 1.
Zanda, Synth. Commun. 1998, 28, 2665.
[7]
[8]
[9]
K. Tanaka, M. Oshuga, Y. Sugimoto, Y. Okafuji, K. Mitsu-
hashi, J. Fluorine Chem. 1988, 39, 39.
M. Ihara, Y. Tanaka, N. Takahashi, Y. Tokunaga, K. Fuku-
moto, J. Chem. Soc., Perkin Trans. 1 1997, 3043.
A. Arnone, M. Cavicchioli, A. Donadelli, G. Resnati, Tetra-
hedron: Asymmetry 1994, 5, 1019; A. Arnone, P. Bravo, A. Do-
nadelli, G. Resnati, Tetrahedron 1996, 52, 131; A. Arnone, P.
[2]
P. Bravo, G. Resnati, Tetrahedron: Asymmetry 1990, 1, 661; Flu-
orine in Bioorganic Chemistry (Ed.: J. T. Welch, S. Eswarakrish-
nan), Wiley, New York, 1991.
´
Bandiera, P. Bravo, L. Bruche, M. Zanda, Gazz. Chim. Ital.
[3]
1996, 126, 773; A. Arnone, F. Blasco, G. Resnati, Tetrahedron
1997, 53, 17513.
1,3-Dipolar Cycloaddition Chemistry (Ed.: A. Padwa), Wiley,
New York, 1984; W. Carruthers, Cycloaddition Reactions in Or-
ganic Synthesis, Pergamon Press, Oxford, 1990.
[10]
P. Bravo, E. Piovosi, G. Resnati, S. De Munari, Gazz. Chim.
Ital. 1988, 118, 115.
[4] [4a]
K. B. G. Torssell, Nitrile Oxides, Nitrones and Nitronates in
[11]
[12]
Organic Synthesis, VCH, New York, 1988. Ϫ [4b] R. Annunziata,
P. Bravo, G. Resnati, Tetrahedron Lett. 1987, 28, 4865.
P. Bravo, E. Piovosi, G. Resnati, J. Chem. Soc., Perkin Trans. 1
1989, 1201.
M. Cinquini, F. Cozzi, L. Raimondi, Gazz. Chim. Ital. 1989,
[4c]
119, 253. Ϫ
M. Cinquini, F. Cozzi, “Stereoselective Syn-
[13]
[14]
[15]
H. Sugihara, R. Tanikaga, A. Kaji, Synthesis 1978, 881.
P. Bravo, M. Frigerio, G. Resnati, J. Org. Chem. 1990, 55, 4216.
P. DeShong, C. M. Dicken, J. M. Leginus, R. R. Whittle, J. Am.
Chem. Soc. 1984, 106, 5598.
thesis” in Methods Org. Chem. (Houben-Weyl), 1995, vol. E21c,
[4d]
ch. 1.6.1.2, p. 2953. Ϫ
M. Frederickson, Tetrahedron 1997,
53, 403. Ϫ [4e] K. V. Gothelf, K. A. Jorgensen, Chem. Rev. 1998,
98, 863.
[16]
[17]
[18]
[5]
´
M. Cherest, H. Felkin, N. Prudent, Tetrahedron Lett. 1968,
P. Bravo, A. Farina, M. Frigerio, S. V. Meille, F. Viani, Tetra-
hedron: Asymmetry 1994, 5, 987 and references therein; P.
2199; N. T. Anh, O. Eisenstein, Nouv. J. Chim. 1977, 1, 61.
´
P. Bravo, L. Bruche, G. Fronza, G. Zecchi, Tetrahedron 1992,
´
Bravo, L. Bruche, M. Frigerio, F. Viani, M. Zanda, Phosphorus
48, 9775.
Sulfur Silicon 1994, 95Ϫ96, 399; P. Bravo, M. Zanda, “Asym-
metric Synthesis of Fluoro Organic Compounds via Chiral Sul-
foxide Chemistry” in Enantiocontrolled Synthesis of Fluoro Or-
ganic Compounds: Stereochemical Challenges and Biomedical
Targets (Ed.: V. A. Soloshonok), Wiley, Chichester, in press.
C. R. Davies, J. S. Davies, J. Chem. Soc., Perkin Trans. 1 1976,
2390; Y.-S. Hon, F.-J. Chang, L. Lu, W.-C. Lin, Tetrahedron
1998, 54, 5233.
Received January 22, 1999
[O99026]
[6]
´
P. Bravo, L. Bruche, A. Farina, G. Fronza, S. V. Meille, A.
1670
Eur. J. Org. Chem. 1999, 1665Ϫ1670