Stereoselective synthesis of trifluoromethyl analogues of polyhydroxypyrrolidines

Article abstract of DOI:10.1002/ejoc.201201599

Incorporation of fluorine atoms into organic molecules significantly enhances many of their properties, such as solubility, metabolic stability, and bioavailability. Among organofluorine molecules, trifluoromethylated compounds play a unique and important role in agricultural and medicinal chemistry. An efficient strategy for the synthesis of a variety of trifluoromethylated polyhydroxypyrrolidines is described. This strategy involves a diastereoselective nucleophilic addition reaciton of trimethyl(trifluoromethyl) silane to sugar-derived cyclic nitrones followed by reductive N-O bond cleavage and removal of benzyl groups. An efficient strategy for the synthesis of a variety of trifluoromethylated polyhydroxypyrrolidines is described. This strategy involves a diastereoselective nucleophilic addition reaction of trimethyl(trifluoromethyl)silane to sugar-derived cyclic nitrones followed by reductive N-O bond cleavage and removal of benzyl groups. Copyright

Full text of DOI:10.1002/ejoc.201201599

Job/Unit: O21599
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Pages: 8
FULL PAPER
DOI: 10.1002/ejoc.201201599
Stereoselective Synthesis of Trifluoromethyl Analogues of
Polyhydroxypyrrolidines
Rama K. Khangarot[a] and Krishna P. Kaliappan*[a]
Keywords: Synthetic methods / Nitrogen heterocycles / Fluorine / Nucleophilic addition / Diastereoselectivity
Incorporation of fluorine atoms into organic molecules
significantly enhances many of their properties, such as solu-
bility, metabolic stability, and bioavailability. Among organo-
fluorine molecules, trifluoromethylated compounds play a
unique and important role in agricultural and medicinal
chemistry. An efficient strategy for the synthesis of a variety
of trifluoromethylated polyhydroxypyrrolidines is described.
This strategy involves a diastereoselective nucleophilic ad-
dition reaciton of trimethyl(trifluoromethyl)silane to sugar-
derived cyclic nitrones followed by reductive N–O bond
cleavage and removal of benzyl groups.
tracted a lot of attention from both synthetic and medicinal
chemists. Among these compounds, codonopsine (1) and
codonopsinine (2) were isolated[7] from Codonopsis clemati-
dea, and 3,4-dihydroxy-2-hydroxymethyl-6-methylpyrrol-
idine [6-deoxy-DMDP (3); an inhibitor of β-mannosidase,
β-galactosidase, and α-fucosidase] was isolated from Angyl-
ocalyx sp. Leguminosae (Figure 1).[8]
Likewise, amines bearing a trifluoromethyl group at the
α-position constitute an important class of biologically
active compounds (Figure 2).[9] The strong electron-with-
drawing nature and large hydrophobic domain of the tri-
fluoromethyl group can significantly influence the basicity
and solubility of amines, thereby modifying the bioavail-
Introduction
Pyrrolidines are commonly found subunits present in
many natural products, especially alkaloids (Figure 1),
which have been isolated from natural sources, including
plants and microorganisms.[1] These compounds have been
shown to exhibit potent and selective inhibitory activities
against biologically-important enzymes such as glycosidases
and other enzymes closely associated with the metabolism
of N-linked glycoproteins.[2] Owing to this biological ac-
tivity, iminocyclitols have potential to become powerful
tools against cancer,[3] viral infections,[4] diabetes[5] and ly-
sosomal storage disorders, and are consequently considered
privileged scaffolds for drug design.[6] An unusual variety of
natural polyhydroxylated pyrrolidines possessing a methyl
group at C-2 of the pyrrolidine system have recently at-
Figure 1. Different polyhydroxypyrrolidine natural products.
[a] Department of Chemistry, Indian Institute of Technology
Bombay,
Powai, Mumbai 400076, India
Fax: +91-22-2572-3480
E-mail: kpk@chem.iitb.ac.in
Homepage: http://www.chem.iitb.ac.in/~kpk/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201599.
Figure 2. Trifluoromethylated amines as natural products.
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R. K. Khangarot, K. P. Kaliappan
FULL PAPER
ability and stability of target drugs. For these reasons, they
have become popular and essential building blocks in the
design and synthesis of fungicides, pesticides, insecticides,
selective antibacterial agents, enzyme inhibitors, and en-
zyme receptor antagonists or agonists.[10] As part of our
studies on sugar-derived cyclic nitrones[11] and fluorinated
compounds,[12] we developed an interest in synthesizing chi-
ral trifluoromethylated analogues of 6-deoxy-DMDP (3).
We intended to take advantage of the availability of a set
of protected hydroxylated cyclic nitrones that can easily be
prepared from carbohydrates, thus providing one or more
stereogenic centers of the pyrrolidine ring (Scheme 1).
Furthermore, several polyhydroxypyrrolidine alkaloids have
been synthesized through diastereoselective nucleophilic ad-
dition reaction of organometallic reagents to sugar-derived
cyclic nitrones.[13]
Scheme 1. Nucleophilic addition reaction of Me3SiCF3 to sugar-
derived cyclic nitrones followed by N–O bond cleavage and removal
of protecting groups.
To introduce the trifluoromethyl group trimethyl(trifluo-
romethyl)silane (Ruppert–Prakash’s reagent)[14] was used, chlorins and bacteriochlorins, carbohydrates, esters, sulf-
because it has been widely used for trifluoromethylation of onic, sulfinic and selenic esters and α-keto esters, amino
aldehydes and ketones, enones and indinones, porphyrins, esters, oxazolidinones, amides and α-keto amides, imines,
Table 1. Nucleophilic addition reaction of Me3SiCF3 to different sugar-derived cyclic nitrones followed by N–O bond cleavage and
removal of protecting groups.
[a] Trifluoromethylated cyclic hydroxylamines were synthesized from the respective cyclic nitrones and Me3SiCF3 by using TBAF in THF
at 0 °C. [b] Trifluoromethylated amines were synthesized from the respective trifluoromethylated cyclic hydroxylamines by using Zn, In,
aq. NH4Cl, MeOH, reflux, 12 h. [c] Trifluoromethylated polyhydroxypyrrolidines were synthesized through removal of protecting groups.
2
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Trifluoromethyl Analogues of Polyhydroxypyrrolidines
thiocyanate and selenocyanate, and organophosphorus subsequently converted into corresponding trifluoromethyl-
compounds.[15] However, little attention has been paid to ated amines 24–27 through cleavage of the N–O bond.
the trifluoromethylation of nitrones.[16]
Removal of the protecting groups was performed on
We started to explore its reactions with electrophilic sugar-derived trifluoromethylated cyclic hydroxylamines
sugar-derived cyclic nitrones (13, ent-13, and 17–19) in the 20–22 to obtain trifluoromethylated polyhydroxylated pyr-
hope of finding new ways of introducing a CF3 group rolidines 28–30. In the case of compound 27 deprotection
stereoselectively into a pyrrolidine ring. To begin with, d- of acetonide groups was carried out in 6 n HCl in MeOH
xylose-derived cyclic nitrone 13 was examined as a model to obtain trifluoromethylated polyhydroxylated pyrrolidine
substrate for direct trifluoromethylation. When a mixture of 31 in 85% yield.
13, Me3SiCF3 (10; 1.0 equiv.), and tetra-n-butylammonium
fluoride (TBAF; 1.5 equiv.) in tetrahydrofuran (THF) was
Conclusions
stirred at 0 °C under a nitrogen atmosphere for 30 min, de-
sired product 14 was formed in 60% yield (Scheme 2). It is
worth mentioning that product 14 resulted from anti attack
of the trifluoromethyl anion with respect to the 4-benzyloxy
group as a result of both steric and stereoelectronic ef-
fects.[17]
In summary, we have illustrated a simple and efficient
route to sugar-based trifluoromethylated cyclic hydroxyl-
amines by using a nucleophilic trifluoromethylation reac-
tion of sugar-derived cyclic nitrones with Ruppert’s reagent,
Me3SiCF3, in the key step. Subsequently, upon reductive
N–O bond cleavage and removal of the protecting groups
these compounds afforded trifluoromethylated analogues of
the natural product 6-deoxy-DMDP. The introduction of a
trifluoromethyl group may significantly improve the bio-
availability of polyhydroxylated pyrrolidines.
Experimental Section
General Methods: Unless otherwise noted, all the starting materials
and reagents were obtained from commercial suppliers and used
after further purification. Tetrahydrofuran was distilled from so-
dium benzophenone ketyl, and toluene from sodium. Dichloro-
methane, hexane and acetonitrile were freshly distilled from cal-
cium hydride. All solvents for routine isolation of products and
chromatography were reagent grade and glass distilled. Air and
moisture sensitive reactions were performed under an argon/UHP
nitrogen atmosphere. Flash chromatography was performed by
using silica gel (100–200 mesh, Aceme) with indicated solvents. All
reactions were monitored by thin-layer chromatography carried out
on 0.25 mm E. Merck silica plates (60F-254) by using UV light as
visualizing agent and 7% ethanolic phosphomolybdic acid and heat
as developing agents. Optical rotations were recorded with a Ru-
dolph Autopol IV digital polarimeter. High-resolution mass spectra
(HRMS) were recorded on a micromass ESI TOF (time of flight)
mass spectrometer. IR spectra were recorded with a Perkin–Elmer
Scheme 2. Nucleophilic addition reaction of Me3SiCF3 to d-xylose-
derived cyclic nitrone followed by N–O bond cleavage and removal
of benzyl groups.
Next we turned our attention to transform cyclic hydrox-
ylamine 14 into corresponding trifluoromethylated amine
15 through cleavage of the N–O bond. Under standard con-
ditions,[18] Zn dust and indium powder in aq. NH4Cl and
MeOH at reflux temperatures for 12 h, smoothly cleaved
the N–O bond and provided desired product 15 in 90%
yield (Table 1).
Finally, removal of the benzyl groups was achieved by
treating with 10% Pd(OH)2/C (Pearlman’s catalyst) in
MeOH/HCl under a hydrogen atmosphere[19] from com-
pound 14 to afford trifluoromethylated polyhydroxylated
pyrrolidine 16 as its salt, which was later neutralized with
IRA-400 resin (OH– form; Scheme 2).
1
Spectrum One FTIR spectrometer. H, 13C and 19F NMR spectra
were recorded with a Bruker AV 400 MHz instrument in CDCl3,
D2O and CD3OD. The following abbreviations are used in re-
porting NMR spectroscopic data: s, singlet; br., broad; d, doublet;
t, triplet; q, quartet; dd, dt, doublet of triplets; td, triplet of dou-
blets; ABq, AB quartet; m, multiplet all of the reported 19F NMR
spectra were recorded with hydrogen decoupling. For compounds
14–15, 20–22 and 24–26 CF3 peaks were not observed on the 13C
NMR spectra owing to the dilute samples.
General Procedure for the Nucleophilic Addition of Me3SiCF3: To a
stirred solution of nitrone (1 mmol) in dry THF (15 mL) was added
trimethyl(trifluoromethyl)silane (1 mmol) and the mixture was co-
oled to 0 °C. Then, a solution of TBAF (1.5 mmol) in THF (4 mL)
was added, and the obtained mixture was stirred at room tempera-
ture for 0.5 h. The completion of the reaction was confirmed by
TLC. After completion of the reaction, the mixture was treated
with dilute aqueous HCl, the organic layer was separated, and the
To investigate the substrate scope, we then performed a
series of reactions of various sugar-derived cyclic nitrones
with Me3SiCF3 (Table 1). Gratifyingly, nitrone 17, ent-13,
18 and 19 on treatment with Me3SiCF3 (10), furnished tri-
fluoromethylated cyclic hydroxylamines 20–23 in good
yields (69, 60, 56 and 63%, respectively; Table 1). Having
successfully synthesized a variety of sugar-derived trifluoro-
methylated cyclic hydroxylamines, these intermediates were aqueous layer was extracted with CH2Cl2 (2ϫ 5 mL). The com-
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R. K. Khangarot, K. P. Kaliappan
FULL PAPER
bined organic extracts were washed with brine, dried with Na2SO4,
filtered and concentrated under vacuum to obtain the crude prod-
uct, which was purified by silica gel flash column chromatography.
4.40 (m, 6 H), 4.13–4.09 (m, 2 H), 3.90 (dd, J = 12.7, 8.1 Hz, 1 H),
3.83 (dd, J = 7.6, 4.6 Hz, 1 H), 3.81–3.70 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 138.1, 137.6, 137.0, 128.6, 128.6, 128.5,
128.2, 128.0, 128.0, 127.9, 127.9, 127.8, 80.1, 79.1, 75.4, 75.1, 74.8,
(2S,3S,4S,5R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-(tri-
fluoromethyl)pyrroli-din-1-ol (14): Following the general procedure,
starting from nitrone 13 (50 mg, 0.12 mmol) and trimethyl(trifluor-
omethyl)silane (10; 17 mg, 0.12 mmol), product 14 was obtained as
a colorless oil (35 mg, 60%) after purification by silica gel column
chromatography (12% ethyl acetate/hexanes). Rf = 0.6 (20% ethyl
2
74.5 (q, J(C–F) = 28.7 Hz), 73.7, 72.1, 71.7, 69.5, 67.1 ppm. 19F
NMR (376 MHz, CDCl ): δ = –73.4 ppm. IR (CHCl ): ν = 3732,
˜
3
3
3375, 2926, 2856, 2397, 2104, 1658, 1455, 1276, 1217, 1126, 1028,
698 cm–1. HRMS: calcd. for C27H28F3NO4 (M + 1)+ 488.2049;
found 488.2054.
acetate/hexanes). [α]2D0
=
9.4 (c
=
1.00, CHCl3). 1H NMR
(3aS,4S,6S,6aR)-4-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2,2-di-
methyl-6-(trifluoromethyl)dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrol-
5(4H)-ol (23): Following the general procedure, starting from
nitrone 19 (100 mg, 0.39 mmol) and trimethyl(trifluoromethyl)si-
(400 MHz, CDCl3): δ = 7.36–7.25 (m, 15 H), 5.34 (br. s, 1 H), 4.55–
4.40 (m, 6 H), 4.11 (dd, J = 5.6, 2.4 Hz, 1 H), 4.09 (t, J = 2.4 Hz,
1 H), 3.92–3.87 (m, 1 H), 3.82 (dd, J = 7.6, 4.7 Hz, 1 H), 3.73–3.68
(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.1, 137.6, lane (10; 56 mg, 0.39 mmol), product 23 was obtained as a colorless
137.3, 128.6, 128.6, 128.5, 128.2, 128.1, 128.0, 127.9, 127.8, 82.4,
oil (80 mg, 63%) after purification by silica gel column chromatog-
raphy (12% ethyl acetate/hexanes). Rf = 0.7 (20% ethyl acetate/
hexanes). [α]2D0 = –24.4 (c = 2.00, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 5.94 (s, 1 H), 4.51 (dd, J = 6.9, 4.4 Hz, 1 H), 4.32 (dd,
J = 12.2, 5.6 Hz, 2 H), 4.08 (dd, J = 8.9, 6.6 Hz, 1 H), 3.99 (dd, J
= 8.9, 4.7 Hz, 1 H), 3.70–3.64 (m, 1 H), 3.26 (t, J = 5.5 Hz, 1 H),
1.56 (s, 3 H), 1.48 (s, 3 H), 1.36 (s, 3 H), 1.31 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 129.1, 126.3, 123.5, 120.8 (q,
1J(C–F) = 277.7 Hz), 114.4, 110.3, 109.9, 76.4, 76.4, 76.1, 74.4, 73.3,
82.2, 73.5, 72.4 (q, 2J(C–F) = 28 Hz), 72.0, 68.9, 65.7 ppm. 19F NMR
(376 MHz, CDCl ): δ = –72.5 ppm. IR (CHCl ): ν = 3712, 3363,
˜
3
3
3013, 2926, 2862, 2343, 2102, 1454, 1364, 1280, 1217, 1166, 1096,
1027, 698, 670 cm–1. HRMS: calcd. for C27H28F3NO4 (M + 1)+
488.2049; found 488.2060.
(2S,3R,4S,5R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-(tri-
fluoromethyl)pyrrolidin-1-ol (20): Following the general procedure,
starting from nitrone 17 (100 mg, 0.24 mmol) and trimethyl(trifluo-
romethyl)silane (10; 34 mg, 0.24 mmol), product 20 was obtained
as a white solid (80 mg, 69%) after purification by silica gel column
chromatography (12% ethyl acetate/hexanes). Rf = 0.6 (20% ethyl
acetate/hexanes), m.p. 87–88 °C. [α]2D0 = –10.5 (c = 2.00, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.36–7.22 (m, 15 H), 5.99 (s, 1
H), 4.73, 4.58 (ABq, J = 11.7 Hz, 2 H), 4.55–4.47 (m, 4 H), 4.07
(t, J = 3.8 Hz, 1 H), 4.00–3.88 (m, 4 H), 3.45 (dd, J = 9.7, 6.0 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.0, 137.8, 137.2,
2
73.0, 72.8, 72.5 (q, J(C–F) = 28.3 Hz), 66.0, 27.4, 26.3, 25.3,
25.3 ppm. 19F NMR (376 MHz, CDCl3): δ = –74.0 ppm. IR
(CHCl ): ν = 3715, 3429, 2991, 2937, 1670, 1460, 1384, 1336, 1270,
˜
3
1216, 1155, 1074, 927, 890, 850, 697 cm–1. HRMS: calcd. for
C13H20F3NO5 (M + 1)+ 328.1372; found 328.1375.
General Procedure for the Cleavage of N–O Bond: Zn powder
(40 mmol) and indium powder (0.01 mmol) were added to a solu-
tion of cyclic hydroxylamine (1 mmol) in a saturated solution of
128.6, 128.5, 128.1, 128.0, 127.9, 127.9, 79.1, 74.7, 74.4, 74.1, 73.8 NH4Cl and MeOH (1:0.8, 30 mL) and the mixture was heated to
2
(q, J(C–F) = 28 Hz), 73.7, 73.6, 73.1, 67.4, 65.3 ppm. 19F NMR 70 °C. After 12 h, the mixture was cooled to room temperature,
(376 MHz, CDCl ): δ = –73.6 ppm. IR (KBr): ν = 3712, 3318, 3029,
and the solvent was evaporated to obtain the residue. Then, EtOAc
was added to the residue and washed with an aqueous solution of
Na2CO3. The organic layer was dried with anhydrous Na2SO4, fil-
tered and concentrated under vacuum to obtain the crude product,
which was purified by basic alumina flash column chromatography.
˜
3
2932, 2873, 2346, 2101, 1457, 1368, 1271, 1235, 1177, 1142, 1114,
1054, 1028, 908, 695 cm–1. HRMS: calcd. for C27H28F3NO4 (M +
1)+ 488.2049; found 488.2040.
(2R,3R,4R,5S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-(trifluoro-
methyl)pyrrolidin-1-ol (21): Following the general procedure, start-
ing from nitrone ent-13 (100 mg, 0.24 mmol) and trimethyl(trifluor-
omethyl)silane (10; 34 mg, 0.24 mmol), product 21 was obtained as
a colorless oil (70 mg, 60%) after purification by silica gel column
(2S,3S,4S,5R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-(tri-
fluoromethyl)pyrrolidine (15): Following the general procedure,
starting from cyclic hydroxylamine 14 (30 mg, 0.06 mmol), product
15 was obtained as a colorless oil (26 mg, 90%) after purification
chromatography (12% ethyl acetate/hexanes). Rf = 0.6 (20% ethyl by basic alumina column chromatography (8% ethyl acetate/hex-
acetate/hexanes). [α]2D0 = –10.5 (c = 2.00, CHCl3). 1H NMR anes). Rf = 0.7 (20% ethyl acetate/hexanes). [α]2D0 = –8.9 (c = 2.00,
(400 MHz, CDCl3): δ = 7.37–7.26 (m, 15 H), 5.60 (s, 1 H), 4.59– CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.38–7.24 (m, 15 H),
4.40 (m, 6 H), 4.13–4.09 (m, 2 H), 3.90 (dd, J = 12.7, 8.1 Hz, 1 H),
4.62–4.42 (m, 6 H), 4.25 (t, J = 4.4 Hz, 1 H), 4.00 (dd, J = 7.4,
3.83 (dd, J = 7.6, 4.6 Hz, 1 H), 3.81–3.70 (m, 2 H) ppm. 13C NMR 4.7 Hz, 1 H), 3.66 (dd, J = 8.5, 3.9 Hz, 1 H), 3.60 (dd, J = 9.7,
(100 MHz, CDCl3): δ = 138.0, 137.6, 137.3, 128.6, 128.5, 128.5, 3.4 Hz, 1 H), 3.49 (dd, J = 9.7, 4.7 Hz, 1 H), 3.35–3.34 (m, 1 H),
128.1, 128.1, 128.0, 127.9, 127.8, 82.4, 82.2, 73.5, 72.7, 72.4, 72.1,
2.17 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.0, 137.9,
2
72.0 (q, J(C–F) = 28 Hz), 68.9, 65.6 ppm. 19F NMR (376 MHz,
137.5, 128.6, 128.6, 128.6, 128.1, 128.0, 128.0, 127.9, 85.2, 84.9,
2
CDCl ): δ = –72.3 ppm. IR (CHCl ): ν = 3736, 3339, 3032, 2930,
82.4, 73.4, 72.6, 72.6, 68.3, 63.6, 63.3 (q, J(C–F) = 30 Hz),
˜
3
3
2859, 2343, 2102, 1455, 1364, 1277, 1216, 1167, 1100, 1028, 61.5 ppm. 19F NMR (376 MHz, CDCl3): δ = –74.9 ppm. IR
698 cm–1. HRMS: calcd. for C27H28F3NO4 (M + 1)+ 488.2049; (CHCl ): ν = 3363, 3013, 2926, 2862, 2343, 2102, 1454, 1364, 1280,
˜
3
found 488.2037.
1217, 1166, 1096, 1027, 698, 670 cm–1. HRMS: calcd. for
C27H28F3NO3 (M + 1)+ 472.2100; found 472.2099.
(2S,3R,4R,5S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-(tri-
fluoromethyl)pyrrolidin-1-ol (22): Following the general procedure,
(2S,3R,4S,5R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-(tri-
starting from nitrone 18 (100 mg, 0.24 mmol) and trimethyl(trifluo- fluoromethyl)pyrrolidine (24): Following the general procedure,
romethyl)silane (10; 34 mg, 0.24 mmol), product 22 was obtained
as a colorless oil (65 mg, 56%) after purification by silica gel col-
umn chromatography (12% ethyl acetate/hexanes). Rf = 0.6 (20%
ethyl acetate/hexanes). [α]2D0 = 17.7 (c = 1.00, CHCl3). 1H NMR
starting from cyclic hydroxylamine 20 (30 mg, 0.06 mmol), product
24 was obtained as a colorless oil (24 mg, 83%) after purification
by basic alumina column chromatography (8% ethyl acetate/hex-
anes). Rf = 0.7 (20% ethyl acetate/hexanes). [α]2D0 = –21.7 (c = 2.00,
(400 MHz, CDCl3): δ = 7.37–7.26 (m, 15 H), 5.60 (s, 1 H), 4.59– CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.36–7.24 (m, 15 H),
4
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Trifluoromethyl Analogues of Polyhydroxypyrrolidines
4.66 (d, J = 11.6 Hz, 1 H), 4.58–4.47 (m, 5 H), 4.08–4.03 (m, 2 H),
3.73 (dd, J = 7.9, 4.4 Hz, 1 H), 3.70–3.63 (m, 2 H), 3.53–3.45 (m,
(150 mg) at room temperature under N2. Then, the reaction flask
was purged with H2 followed by addition of 10 drops of conc. HCl,
1 H), 2.27 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = and the reaction mixture was stirred for 24 h at room temperature
138.1, 138.1, 137.5, 128.6, 128.5, 128.0, 127.9, 127.9, 79.2, 78.2,
under H2 atmosphere. The mixture was then filtered through a pad
of Celite, and the filtrate was concentrated in vacuo. The residue
2
73.8, 73.4, 73.4, 72.8, 69.0, 62.8, 62.5, 62.2, 61.9 (q, J(C–F)
=
29.3 Hz), 59.4 ppm. 19F NMR (376 MHz, CDCl3): δ = –75.9 ppm. was dissolved in a minimum amount of H2O and stirred with IRA-
IR (CHCl ): ν = 3362, 3029, 2925, 2857, 2328, 1651, 1455, 1370, 400 resin (OH– form) until it reached pH 11. After filtration, the
˜
3
1279, 1217, 1158, 1123, 1112, 915, 698 cm–1. HRMS: calcd. for
C27H28F3NO3 (M + 1)+ 472.2100; found 472.2090.
filtrate was concentrated in vacuo to give pure trifluoromethylated
polyhydroxylated pyrrolidine.
(2R,3R,4R,5S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-(trifluoro-
methyl)pyrrolidine (25): Following the general procedure, starting
from cyclic hydroxylamine 21 (30 mg, 0.06 mmol), product 25 was
obtained as a colorless oil (27 mg, 93%) after purification by basic
alumina column chromatography (8% ethyl acetate/hexanes). Rf =
0.7 (20% ethyl acetate/hexanes). [α]2D0 = 18.4 (c = 2.00, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.37–7.24 (m, 1 H), 4.62–4.42 (m, 6
H), 4.25 (t, J = 4.4 Hz, 1 H), 4.00 (dd, J = 7.6, 4.8 Hz, 1 H), 3.64
(bd, J = 4.9 Hz, 1 H), 3.60 (dd, J = 9.7, 3.4 Hz, 1 H), 3.49 (dd, J
= 9.7, 4.6 Hz, 1 H), 3.34 (br. s, 1 H), 2.55 (br. s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 138.0, 137.9, 137.5, 128.6, 128.6,
128.5, 128.1, 128.0, 128.0, 128.0, 85.2, 84.9, 73.4, 72.6, 72.6, 68.4,
(2S,3S,4S,5R)-2-(Hydroxymethyl)-5-(trifluoromethyl)pyrrolidine-
3,4-diol (16): Following the general procedure, starting from cyclic
hydroxylamine 14 (80 mg, 0.16 mmol), product 16 was obtained as
a white solid (31 mg, 95%). Rf = 0.4 (100% ethyl acetate), m.p.
159–160 °C. [α]2D0 = –4.1 (c = 2.00, H2O). 1H NMR (400 MHz,
D2O): δ = 4.24 (t, J = 7.2 Hz, 1 H), 3.87 (t, J = 8.2 Hz, 1 H), 3.75–
3.66 (m, 2 H), 3.63 (t, J = 7.8 Hz, 1 H), 2.95–2.93 (m, 1 H) ppm.
1
13C NMR (100 MHz, D2O): δ = 127.3, 124.5 (q, J(C–F) = 277 Hz),
2
76.5, 68.4, 61.6, 61.4, 61.3, 61.0, 60.7 (q, J(C–F) = 29 Hz),
59.6 ppm. 19F NMR (376 MHz, D2O): δ = –75.8 ppm. IR (KBr):
ν = 3366, 2924, 2868, 1657, 1455, 1261, 1186, 1029, 976, 823,
˜
751 cm–1. HRMS: calcd. for C6H10F3NO3 (M + 1)+ 202.0691;
found 202.0694.
2
63.6, 63.3 (q, J(C–F) = 29 Hz), 61.5 ppm. 19F NMR (376 MHz,
CDCl ): δ = –74.9 ppm. IR (CHCl ): ν = 3347, 3064, 3032, 2917,
˜
3
3
(2S,3R,4S,5R)-2-(Hydroxymethyl)-5-(trifluoromethyl)pyrrolidine-
3,4-diol (28): Following the general procedure, starting from cyclic
hydroxylamine 20 (90 mg, 0.18 mmol), product 28 was obtained as
2862, 2109, 1496, 1454, 1363, 1279, 1208, 1163, 1134, 1108, 1028,
912, 858, 698 cm–1. HRMS: calcd. for C27H28F3NO3 (M + 1)+
472.2100; found 472.2098.
a colorless oil (36 mg, 94%). Rf = 0.4 (100% ethyl acetate). [α]2D0
=
(2S,3R,4R,5S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-(tri-
fluoromethyl)pyrrolidine (26): Following the general procedure,
starting from cyclic hydroxylamine 22 (30 mg, 0.06 mmol), product
26 was obtained as a colorless oil (25 mg, 86%) after purification
by basic alumina column chromatography (8% ethyl acetate/hex-
anes). Rf = 0.7 (20% ethyl acetate/hexanes). [α]2D0 = 13.4 (c = 1.00,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.37–7.25 (m, 15 H),
4.58–4.40 (m, 6 H), 4.07 (dd, J = 3.4, 1.2 Hz, 1 H), 3.91 (d, J =
2.0 Hz, 1 H), 3.74 (dd, J = 8.6, 4.7 Hz, 1 H), 3.69–3.62 (m, 3 H),
3.59 (dd, J = 7.3, 4.7 Hz, 1 H), 2.30 (br. s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 138.2, 137.9, 137.4, 128.6, 128.6, 128.1,
128.0, 127.9, 127.8, 127.8, 82.5, 81.8, 73.7, 72.0, 71.7, 69.8, 65.6,
1
–5.9 (c = 2.00, H2O). H NMR (400 MHz, D2O): δ = 4.41 (dd, J
= 7.5, 4.1 Hz, 1 H), 4.14 (t, J = 3.1 Hz, 1 H), 3.76 (dd, J = 11.3,
6.9 Hz, 1 H), 3.68–3.61 (m, 2 H), 3.18 (td, J = 6.4, 2.9 Hz, 1
H) ppm. 13C NMR (100 MHz, D2O): δ = 130.5, 127.7, 125.0, 122.2
1
(q, J(C–F) = 277 Hz), 73.0, 72.2, 62.4, 62.1, 61.9, 61.6, 61.3 (q,
2J(C–F) = 29 Hz), 60.8, 59.3 ppm. 19F NMR (376 MHz, D2O): δ =
–75.4 ppm. IR (neat): ν = 3363, 2924, 2851, 1656, 1452, 1262, 1020,
˜
913, 826, 757 cm–1. HRMS: calcd. for C6H10F3NO3 (M + 1)+
202.0691; found 202.0687.
(2R,3R,4R,5S)-2-(Hydroxymethyl)-5-(trifluoromethyl)pyrrolidine-
3,4-diol (29): Following the general procedure, starting from cyclic
hydroxylamine 21 (80 mg, 0.16 mmol), product 29 was obtained as
2
65.3, 65.0, 64.7 (q, J(C–F) = 30 Hz), 60.7 ppm. 19F NMR
a colorless oil (29 mg, 92%). Rf = 0.4 (100% ethyl acetate). [α]2D0
=
(376 MHz, CDCl ): δ = –74.6 ppm. IR (CHCl ): ν = 3736, 3280,
˜
3
3
1
3.5 (c = 2.00, H2O). H NMR (400 MHz, D2O): δ = 4.21 (t, J =
7.3 Hz, 1 H), 3.84 (t, J = 8.0 Hz, 1 H), 3.71 (s, 1 H), 3.69–3.66
3032, 2932, 2860, 2361, 1657, 1455, 1405, 1086, 1052, 1028,
697 cm–1. HRMS: calcd. for C27H28F3NO3 (M + 1)+ 472.2100;
found 472. 2085.
(m, 1 H), 3.64–3.58 (m, 1 H), 3.06–2.89 (m, 1 H) ppm. 13C NMR
1
(100 MHz, D2O): δ = 130.1, 127.3, 124.4, 122.1 (q, J(C–F)
=
(3aS,4S,6S,6aR)-4-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2,2-di-
methyl-6-(trifluoromethyl)tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrole
(27): Following the general procedure, starting from cyclic hydrox-
ylamine 23 (30 mg, 0.09 mmol), product 27 was obtained as a col-
orless oil (22 mg, 77%) after purification by basic alumina column
chromatography (6% ethyl acetate/hexanes). Rf = 0.8 (20% ethyl
acetate/hexanes). [α]2D0 = –19.3 (c = 2.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 4.66 (dd, J = 6.7, 3.5 Hz, 1 H), 4.29 (t, J
= 6.2 Hz, 1 H), 4.11–4.04 (m, 2 H), 3.86–3.81 (m, 1 H), 3.74 (bt, J
= 3.3 Hz, 1 H), 3.24 (br. s, 1 H), 2.38 (br. s, 1 H), 1.53 (s, 3 H),
1.43 (s, 3 H), 1.35 (s, 3 H), 1.33 (s, 3 H) ppm. 13C NMR (100 MHz,
277 Hz), 76.6, 66.5, 61.7, 61.5, 61.4, 61.1, 60.8 (q, 2J(C–F) = 29 Hz),
59.7 ppm. 19F NMR (376 MHz, D2O): δ = –75.9 ppm. IR (neat):
ν = 3467, 2925, 1655, 1454, 1284, 1215, 940, 760, 695 cm–1. HRMS:
˜
calcd. for C6H10F3NO3 (M + 1)+ 202.0691; found 202.0696.
(2S,3R,4R,5S)-2-(Hydroxymethyl)-5-(trifluoromethyl)pyrrolidine-
3,4-diol (30): Following the general procedure, starting from cyclic
hydroxylamine 22 (60 mg, 0.12 mmol), product 30 was obtained as
a white solid (22 mg, 88%). Rf = 0.4 (100% ethyl acetate), m.p.
172–173 °C. [α]2D0 = 4.8 (c = 2.00, H2O). 1H NMR (400 MHz,
CD3OD): δ = 4.35 (d, J = 2.4 Hz, 1 H), 4.14 (s, 1 H), 4.07 (dd, J
1
= 8.4, 2.3 Hz, 1 H), 4.04–3.93 (m, 2 H), 3.85–3.82 (m, 1 H) ppm.
CDCl3): δ = 126.5, 123.8 (q, J(C–F) = 277 Hz), 114.5, 109.7, 80.8,
1
13C NMR (100 MHz, CD3OD): δ = 125.8, 123.0 (q, J(C–F)
=
=
2
80.0, 79.9, 78.1, 66.6, 66.2, 64.8, 64.6, 64.2, 64.0 (q, J(C–F)
=
2
29.3 Hz), 27.5, 26.8, 25.4, 25.3 ppm. 19F NMR (376 MHz, CDCl3):
276 Hz), 77.4, 76.4, 68.0, 67.7, 67.5, 67.3, 67.0 (q, J(C–F)
32.7 Hz) ppm. 19F NMR (376 MHz, CD3OD): δ = –72.2 ppm. IR
δ = –75.8 ppm. IR (CHCl ): ν = 3366, 2990, 2938, 1661, 1457, 1383,
˜
3
1375, 1292, 1271, 1216, 1158, 1141, 1071, 969, 889, 853, 693 cm–1.
HRMS: calcd. for C13H20F3NO4 (M + 1)+ 312.1423; found
312.1423.
(KBr): ν = 3380, 2928, 2868, 1661, 1459, 1261, 1109, 802, 765,
˜
716 cm–1. HRMS: calcd. for C6H10F3NO3 (M + 1)+ 202.0691;
found 202.0691.
General Procedure for Hydrogenolysis: To a solution of cyclic hy-
droxylamine (1.00 mmol) in MeOH was added 10% Pd(OH)2/C
(2S,3S,4R,5S)-2-[(S)-1,2-Dihydroxyethyl]-5-(trifluoromethyl)-
pyrrolidine-3,4-diol (31): To a solution of trifluoromethylated amine
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Job/Unit: O21599
/KAP1
Date: 08-03-13 10:32:05
Pages: 8
R. K. Khangarot, K. P. Kaliappan
FULL PAPER
[7]
[8]
27 (80 mg, 0.26 mmol) in MeOH (2.5 mL) was added aq. HCl (6 n,
2.5 mL) at room temperature and stirred for 24 h. Then the solvent
was removed in vacuo, and the residue was dissolved in minimum
amount of H2O and stirred with IRA-400 resin (OH– form) until
pH 11. After filtration, the filtrate was concentrated in vacuo to
give pure trifluoromethylated polyhydroxylated pyrrolidine 31 as
a) S. F. Matkhalikova, V. M. Malikov, S. Y. Yunusov, Khim.
Prir. Soedin. 1969, 5, 606–607; b) S. F. Matkhalikova, V. M.
Malikov, S. Y. Yunusov, Khim. Prir. Soedin. 1969, 5, 30–32.
a) K. Yasuda, H. Kizu, T. Yamashita, Y. Kameda, A. Kato,
R. J. Nash, G. W. J. Fleet, R. J. Molyneux, N. Asano, J. Nat.
Prod. 2002, 65, 198–202; b) R. J. Molyneux, Y. T. Pan, J. E.
Tropea, A. D. Elbein, C. H. Lawyer, D. J. Hughes, G. W. J.
Fleet, J. Nat. Prod. 1993, 56, 1356–1364.
a) P. D. O’Shea, C.-y. Chen, D. Gauvreau, F. Gosselin, G.
Hughes, C. Nadeau, R. P. Volante, J. Org. Chem. 2009, 74,
1605–1610; b) S. Léger, C. I. Bayly, W. C. Black, S. Desmarais,
J.-P. Falgueyret, F. Massé, M. D. Percival, J.-F. Truchon, Bi-
oorg. Med. Chem. Lett. 2007, 17, 4328–4332; c) G. L. Grune-
wald, J. Lu, K. R. Criscione, C. O. Okoro, Bioorg. Med. Chem.
Lett. 2005, 15, 5319–5323; d) N. C. Yoder, K. Kumar, Chem.
Soc. Rev. 2002, 31, 335–341; e) A. Sutherland, C. L. Willis, Nat.
Prod. Rep. 2000, 17, 621–631; f) W. S. Faraci, C. T. Walsh, Bio-
chemistry 1989, 28, 431–437.
a) R. Smits, C. D. Cadicamoo, K. Burger, B. Koksch, Chem.
Soc. Rev. 2008, 37, 1727–1739; b) K. L. Kirk, J. Fluorine Chem.
2006, 127, 1013–1029; c) W. R. Dolbier Jr., J. Fluorine Chem.
2005, 126, 157–163; d) X.-L. Qiu, W.-D. Meng, F.-L. Qing,
Tetrahedron 2004, 60, 6711–6745.
colorless oil (29 mg, 85%). Rf = 0.3 (100% ethyl acetate). [α]2D0
=
1
–12.6 (c = 1.00, H2O). H NMR (400 MHz, D2O): δ = 4.28 (dd, J
= 5.2, 4.3 Hz, 1 H), 3.98 (t, J = 6.2 Hz, 1 H), 3.73–3.63 (m, 3 H),
[9]
3.59–3.52 (m, 1 H), 3.17 (dd, J = 6.7, 4.9 Hz, 1 H) ppm. 13C NMR
1
(100 MHz, D2O): δ = 129.7, 126.9, 124.1, 121.4 (q, J(C–F)
=
2
277.7 Hz), 72.0, 71.8, 70.9, 63.6, 63.3. 63.0 (q, J(C–F) = 29 Hz),
62.4 ppm. 19F NMR (376 MHz, D2O): δ = –75.2 ppm. IR (neat):
ν = 3437, 2924, 2857, 1658, 1455, 1262, 1146, 1093, 1016, 970, 875,
˜
800, 751 cm–1. HRMS: calcd. for C7H12F3NO4 (M + 1)+ 232.0797;
found 232.0798.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data including 1H, 13C NMR and 19F NMR
spectra for all compounds.
[10]
[11]
Acknowledgments
a) A. Bandaru, K. P. Kaliappan, Synlett 2012, 23, 1473–1476;
b) R. K. Khangarot, K. P. Kaliappan, Eur. J. Org. Chem. 2011,
6117–6127; c) K. P. Kaliappan, P. Das, S. T. Chavan, S. G. Sab-
harwal, J. Org. Chem. 2009, 74, 6266–6274; d) K. P. Kaliappan,
P. D a s, Synlett 2008, 841–844.
S. A. Pujari, K. P. Kaliappan, A. Valleix, D. Grée, R. Grée,
Synlett 2008, 2503–2507.
We thank Department of Science and Technology (DST), New
Delhi for financial support. K. P. K acknowledges DST for the
award of Swanajayanti Fellowship. R. K. K. thanks Council of Sci-
entific and Industrial Research (CSIR), New Delhi for a fellowship.
[12]
[13]
a) W. Zhang, K. Sato, A. Kato, Y.-M. Jia, X.-G. Hu, F. X.
Wilson, R. v. Well, G. Horne, G. W. J. Fleet, R. J. Nash, C.-Y.
Yu, Org. Lett. 2011, 13, 4414–4417; b) I. Delso, T. Tejero, A.
Goti, P. Merino, J. Org. Chem. 2011, 76, 4139–4143; c) I. Delso,
E. Marca, V. Mannucci, T. Tejero, A. Goti, P. Merino, Chem.
Eur. J. 2010, 16, 9910–9919; d) M. Marradi, S. Cicchi, J. I.
Delso, L. Rosi, T. Tejero, P. Merino, A. Goti, Tetrahedron Lett.
2005, 46, 1287–1290; e) P. Merino, J. Revuelta, T. Tejero, S.
Cicchi, A. Goti, Eur. J. Org. Chem. 2004, 776–782; f) P. Merino,
T. Tejero, J. Revuelta, P. Romero, S. Cicchi, V. Mannucci, A.
Brandi, A. Goti, Tetrahedron: Asymmetry 2003, 14, 367–379;
g) M. Lombardo, S. Fabbroni, C. Trombini, J. Org. Chem.
2001, 66, 1264–1268; h) R. Ballini, E. Marcantoni, M. Petrini,
J. Org. Chem. 1992, 57, 1316–1318.
a) G. K. S. Prakash, S. Chacko, Curr. Opin. Drug Discovery
Dev. 2008, 11, 793–802, and references cited therein; b) N. Shi-
bata, S. Mizuta, H. Kawai, Tetrahedron: Asymmetry 2008, 19,
2633–2644; c) G. K. S. Prakash, M. Mandal, G. A. Olah, An-
gew. Chem. 2001, 113, 609–610; Angew. Chem. Int. Ed. 2001,
40, 589–590; d) G. K. S. Prakash, M. Mandal, J. Fluorine
Chem. 2001, 112, 123–131; e) G. K. S. Prakash, A. K. Yudin,
Chem. Rev. 1997, 97, 757–786; f) R. Krishnamurti, D. R.
Bellew, G. K. S. Prakash, J. Org. Chem. 1991, 56, 984–989; g)
G. K. S. Prakash, R. Krishnamurti, G. A. Olah, J. Am. Chem.
Soc. 1989, 111, 393–395; h) I. Ruppert, K. Schlich, W. Volbach,
Tetrahedron Lett. 1984, 25, 2195–2198.
a) N. Allendörfer, M. Es-Sayed, M. Nieger, S. Bräse, Tetrahe-
dron Lett. 2012, 53, 388–391; b) R. Kowalczyk, A. J. F. Ed-
munds, R. G. Hall, G. Bolm, Org. Lett. 2011, 13, 768–771; c)
N. E. Shevchenko, K. Vlasov, V. G. Nenajdenko, G.-V.
Röschenthaler, Tetrahedron 2011, 67, 69–74; d) A. D. Dilman,
D. E. Arkhipov, V. V. Levin, P. A. Belyakov, A. A. Korlyukov,
M. I. Struchkova, V. A. Tartakovsky, J. Org. Chem. 2000, 65,
8848–8856; e) J.-C. Blazejewski, E. Anselmi, M. P. Wilmshurst,
Tetrahedron Lett. 1999, 40, 5475–5478; f) Y. Yokoyama, K.
Mochida, Tetrahedron Lett. 1997, 38, 3443–3446. For reviews
on trifluoromethylation with Me3SiCF3, see: g) J.-A. Ma, D.
Cahard, Chem. Rev. 2004, 104, 6119–6146; h) R. P. Singh, J. M.
Shreeve, Tetrahedron 2000, 56, 7613–7632.
[1] a) O. R. Martin, Ann. Pharm. Fr. 2007, 65, 5–13; b) A. A. Wat-
son, G. W. J. Fleet, N. Asano, R. J. Molyneux, R. J. Nash, Phy-
tochemistry 2001, 56, 265–295; c) N. Asano, R. J. Nash, R. J.
Molyneux, G. W. J. Fleet, Tetrahedron: Asymmetry 2000, 11,
1645–1680; d) A. Mitchinson, A. Nadin, J. Chem. Soc. Perkin
Trans. 1 2000, 2862–2892; e) A. B. Mauger, J. Nat. Prod. 1996,
59, 1205–1211; f) T. Shibata, O. Nakayama, Y. Tsurumi, M.
Okuhara, H. Terano, M. Kohsaka, J. Antibiot. 1988, 41, 296–
301; g) R. J. Nash, E. A. Bell, J. M. Williams, Phytochemistry
1985, 24, 1620–1622; h) D. W. C. Jones, R. J. Nash, E. A. Bell,
J. M. Williams, Tetrahedron Lett. 1985, 26, 3125–3126; i) J. Fu-
rukawa, S. Okuda, K. Saito, S.-I. Hatanaka, Phytochemistry
1985, 24, 593–594; j) A. Welter, J. Jadot, G. Dardenne, M.
Marlier, J. Casimir, Phytochemistry 1976, 15, 747–749; k) B. A.
Sobin, F. W. Tanner Jr., J. Am. Chem. Soc. 1954, 76, 4053.
[2] a) P. Compain, O. R. Martin, Iminosugars: From Synthesis to
Therapeutic Applications, Wiley, Chichester, UK, 2007; b) N.
Asano, Glycobiology 2003, 13, 93R–104R; c) Y. Nishimura,
Curr. Top. Med. Chem. 2003, 3, 575–591; d) A. E. Stütz, Imi-
nosugars as Glycosidase Inhibitors: Nojirimycin and Beyond,
Wiley-VCH, Weinheim, Germany, 1999; e) G. S. Jacob, Curr.
Op. Struct. Biol. 1995, 5, 605–611.
[3] a) H. Fiaux, D. A. Kuntz, D. Hoffman, R. C. Janzer, S. Gerber-
Lemaire, D. R. Rose, L. Juillerat-Jeanneret, Bioorg. Med.
Chem. 2008, 16, 7337–7346; b) S. D. Naik, R. Y. Ambaye, S. V.
Gokhale, Anticancer Res. 1987, 7, 87–90.
[4] a) Y. Tanaka, J. Kato, M. Kohara, M. S. Galinski, Antiviral
Res. 2006, 72, 1–9; b) I. Robina, A. J. Moreno-Vargas, A. T.
Carmona, P. Vogel, Curr. Drug Metab. 2004, 5, 329–361; c) N.
Asano, M. Nishida, A. Kato, H. Kizu, K. Matsui, Y. Shimada,
T. Itoh, M. Baba, A. A. Watson, R. J. Nash, P. M. de Lilley,
D. J. Watkin, G. W. J. Fleet, J. Med. Chem. 1998, 41, 2565–
2571.
[14]
[15]
[5] K. A. Watson, E. P. Mitchell, L. N. Johnson, J. C. Son, C. J. F.
Bichard, M. G. Orchard, G. W. J. Fleet, N. G. Oikonomakos,
D. D. Leonidas, M. Kontou, A. Papageorgioui, Biochemistry
1994, 33, 5745–5758.
[6] W. Meutermans, G. T. Le, B. Becker, ChemMedChem 2006, 1,
1164–1194.
6
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Job/Unit: O21599
/KAP1
Date: 08-03-13 10:32:05
Pages: 8
Trifluoromethyl Analogues of Polyhydroxypyrrolidines
[16] a) Y. Chuyi, L. Yixian, J. Yuemei, Faming Zhuanli Shenqing
2011, CN 102199116 A 20110928; b) D. W. Nelson, J. Owens,
D. Hiraldo, J. Org. Chem. 2001, 66, 2572–2582; c) D. W. Nel-
son, R. A. Easley, B. N. V. Pintea, Tetrahedron Lett. 1999, 40,
25–28.
V. G. Puranik, C. V. Ramana, Tetrahedron Lett. 2006, 47, 6979–
6981; f) A. Toyao, O. Tamura, H. Takagi, H. Ishibashi, Synlett
2003, 35–38.
S. Cicchi, M. Bonanni, F. Cardona, J. Revuelta, A. Goti, Org.
Lett. 2003, 5, 1773–1776.
[18]
[17] a) E.-L. Tsou, S.-Y. Chen, M.-H. Yang, S.-C. Wang, T.-R. R.
Cheng, W.-C. Cheng, Bioorg. Med. Chem. 2008, 16, 10198–
10204; b) P. Merino, I. Delso, T. Tejero, F. Cardona, M. Mar-
radi, E. Faggi, C. Parmeggiani, A. Goti, Eur. J. Org. Chem.
2008, 2929–2947; c) P. Merino, I. Delso, T. Tejero, F. Cardona,
A. Goti, Synlett 2007, 2651–2654; d) C.-Y. Yu, M.-H. Huang,
Org. Lett. 2006, 8, 3021–3024; e) M. K. Gurjar, R. G. Borhade,
[19] a) P. Merino, I. Delso, T. Tejero, F. Cardona, M. Marradi, E.
Faggi, C. Parmeggiani, A. Goti, Eur. J. Org. Chem. 2008, 2929–
2947; b) P. Merino, I. Delso, T. Tejero, F. Cardona, A. Goti,
Synlett 2007, 2651–2654.
Received: November 27, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7

Job/Unit: O21599
/KAP1
Date: 08-03-13 10:32:05
Pages: 8
R. K. Khangarot, K. P. Kaliappan
FULL PAPER
Stereoselective Synthesis
R. K. Khangarot, K. P. Kaliappan* ... 1–8
Stereoselective Synthesis of Trifluoro-
methyl Analogues of Polyhydroxypyrrolid-
ines
An efficient strategy for the synthesis of a
variety of trifluoromethylated polyhydroxy-
pyrrolidines is described. This strategy in-
addition reaction of trimethyl(trifluorome-
thyl)silane to sugar-derived cyclic nitrones
followed by reductive N–O bond cleavage
and removal of benzyl groups.
Keywords: Synthetic methods / Nitrogen
heterocycles / Fluorine / Nucleophilic ad-
dition / Diastereoselectivity
volves
a diastereoselective nucleophilic
8
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