Difluorotetrahydropyridothiazinone: A selective β-Galactosidase Inhibitor

Article abstract of DOI:10.1002/ardp.200900307

Selective difluorination, introducing a lactame moiety (instead of an amine) and a double bond in a trihydroxy-2-thiaquinolizidine derivative reverses the selectivity of the glycosidase inhibitor-a selective inhibitor for an α-glucosidase is altered into

Full text of DOI:10.1002/ardp.200900307

Arch. Pharm. Chem. Life Sci. 2010, 10, 577–582
577
Full Paper
Difluorotetrahydropyridothiazinone: A Selective
b-Galactosidase Inhibitor
´
Rene Csuk and Erik Prell
¨
Martin-Luther-Universitat Halle-Wittenberg, Organische Chemie, Halle (Saale), Germany
Selective difluorination, introducing a lactame moiety (instead of an amine) and a double bond in
a trihydroxy-2-thiaquinolizidine derivative reverses the selectivity of the glycosidase inhibitor – a
selective inhibitor for an a-glucosidase is altered into an excellent, competitive inhibitor for a b-
galactosidase.
Keywords: Galactosidase / Galactosidase inhibitor / Glycosidase inhibitor
Received: December 16, 2009; Accepted: April 7, 2010
DOI 10.1002/ardp.200900307
Introduction
pronounced activity in anti-inflammatory macrophage
colony-stimulating factor-1 receptor inhibition [9] as well
as novel histamine-3 receptor inverse agonists [10, 11].
Since rigidity seems to be essential for selectivity in the
inhibition of glycosidases [7], we set out for the synthesis of a
target compound derived from lead structure II but possess-
ing a lactame moiety as well as a geminal difluoromethylene
group in b-position to the ring nitrogen. An extra double
bond in the ring should further reduce the flexibility of
the molecule.
Hyperglycemia and hyperlipidemia are recognized and severe
health-care problems. Obesity is a major risk to develop [1, 2]
coronary artery diseases and hypertension, dyslipidemia and
hyperglycemia as well as cancer. Today, more than 120 million
people are considered obese [3] and the market expenditures
for drugs are expected [4] to increase to over US$ 120 billion by
2010. The use of iminosugars has a long tradition in the
therapy of diabetes [5] and metabolic disorders [6]; miglitol
(I, Fig. 1) is a blockbuster in this field.
Well-known compound 1 [12] (Scheme 1) was deprotected
[13] to afford 82% of 2, whose hydrogenolysis [14–16] gave the
2,2-difluoro-b-D-arabino-hexopyranoside 3 in 94% yield. A
slightly higher yield of 3 was obtained by the hydrogenolysis
of 1 in the presence of Pd/C. Compound 3 is characterized
Several years ago, trihydroxy-2-thiaquinolizidines were
introduced [7] as a new class of bicyclic iminohexitol glyco-
sidase inhibitors and one of these derivatives (II) was shown
to be active only against a-glucosidases. The activity of these
compounds was low as compared, for example to miglitol.
Recently, we were able to show [8] that mono- or difluorina-
tion of iminosugars leads to a dramatic change of activity and
selectivity.
by its 19F-NMR spectrum by the presence of two signals at
2
d ¼ ꢀ124.21 and ꢀ143.19 ppm showing a large JF,F
¼
245.7 Hz. In the 13C-NMR spectrum, geminal difluorinated
1
C(2) was found at d ¼ 117.0 ppm showing JC,F ¼ 253.6 Hz.
Tritylation [17–19] of 3 gave the 6-O-trityl derivative 4
whose pivaloylation [20–22] gave 74% of fully protected 5.
Detritylation [23, 24] of 5 was performed using trimethylsilyl
iodide in dry dichloromethane and 6 was obtained in almost
quantitative yield. Bromination of 6 proceeded smoothly
using triphenylphosphane/tetrabromomethane [25] and
the corresponding 6-bromo-2,2-difluoro-hexopyranoside 7
was obtained in 98% yield (isolated).
Results and discussion
Recently, introducing a geminal difluoromethylene group at
position-3 in a piperidine ring attracted notable interest.
Compounds owning this feature have been shown to display
´
Correspondence: Prof. Dr. Rene Csuk, Bereich Organische Chemie,
Martin-Luther-Universitat Halle-Wittenberg, Kurt-Mothes-Strasse 2, D-
Oxidative ring opening was performed following the
original procedure of Angyal [26, 27]. Thus, treating 7 with
CrO3 (Scheme 2) in a mixture of acetic acid and acetic anhy-
dride provided 68% of acyclic methyl hex-5-ulosonate 8. In its
19F-NMR, compound 8 shows two signals at d ¼ ꢀ111.16 and
¨
06120 Halle (Saale), Germany.
E-mail: rene.csuk@chemie.uni-halle.de
Fax: þ49 345 552-7030
Abbreviation: dialkylaminopyridine (DMAP)
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

578
R. Csuk and E. Prell
Arch. Pharm. Chem. Life Sci. 2010, 10, 577–582
Figure 1. Structure of a-glucosidase inhibitors miglitol I and a 2-
thiaquinolizidine (II, [7]).
2
ꢀ118.04 ppm possessing a JF,F ¼ 270.4 Hz. The 13C-NMR
spectrum shows C(5) at d ¼ 194.7 ppm and the ester carbonyl
2
at d ¼ 162.2 ppm (this signal displays two JC,F of 30.2 and
32.7 Hz, respectively).
The reaction of 8 with cysteamine [7] furnished 9 as the
main product. As by-products an inseparable mixture of 10
was obtained in 24% yield as well 18% of 11 resulting from an
elimination reaction. The structures of 10 and 11 can be
assigned unambiguously from the 13C-NMR spectra. For
C(5), compound 9 shows a chemical shift at d ¼ 124.9 ppm
whereas for C(5) in 11 d ¼ 149.3 ppm is detected; C(4) is
found at d ¼ 100.9 ppm. Finally, compound 9 was depro-
tected using sodium methoxide in methanol [28] and 12
was obtained in 94% yield.
Scheme 2. Synthesis of compounds 8–12.
castanospermine, or swainsonine with nitrogen instead
of the ring oxygen are selective inhibitors [30] for a-
glucosidases. The presence of a lactame instead of an amine,
however, makes 12 less attractive for a-glucosidases. The
specificity of 12 is a starting point to develop even stronger
but still selective inhibitors for b-galactosidases. This might
be of some interest in the therapy of lysosomal storage
disorders.
Compound 12 was tested against several glycosidases [29]
using the p-nitrophenolate assay. Thus, 12 showed no
inhibition at all for the a-glucosidase from Bacillus stearother-
mophilus, the b-glucosidase from almonds, and the a-galacto-
sidase from green coffee beans, but is a competitive inhibitor
for a b-galactosidase from E. coli showing an IC50 of 2.01 mM.
Compound 12 owns a rigid bicyclic structure and seems to be
locked in its conformation (as indicated by semi-empirical
PM3-calculations using the CAChe 4.0 software from Oxford
Molecular) – this results in inactivity against b-glycosidases.
Usually, compounds derived from 1-deoxynojirimycin,
Experimental
General
Melting points are uncorrected (Leica hot stage microscope;
Leica, Wetzlar, Germany), NMR spectra were recorded using
the Varian spectrometers (Varian, USA) Gemini 200, Gemini
2000, or Unity 500 (d given in ppm, J in Hz, internal Me4Si or
internal CCl3F), optical rotations were obtained using a Perkin-
Elmer 341 polarimeter (1 cm micro cell, 208C; Perkin-Elmer,
USA), IR spectra (film or KBr pellet) on a Perkin-Elmer FT-IR
spectrometer Spectrum 1000, MS spectra were taken on a
Intectra GmbH AMD 402 (electron impact, 70 eV; Intectra
GmbH, Harpstedt, Germany) or on a Finnigan MAT TSQ 7000
(electrospray, voltage 4.5 kV, sheath gas nitrogen; Thermo
Scientific, Germany) instrument. TLC was performed on silica
gel (Merck 5554, detection by UV absorption; Merck, Germany).
The solvents were dried according to usual procedures.
Biological evaluation
The p-nitrophenolate assay was performed as a microtiter plate
assay using a Tecan instrument. The a-glucosidase (from Bacillus
stearothermophilus) was obtained from Sigma (96 U/mg; Sigma-
Aldrich, Steinheim, Germany), b-glucosidase (almonds) was
obtained from Fluka (8.92 U/mg; Sigma-Aldrich), a-galactosidase
(green coffee beans) was from Sigma (45.6 U/mL) and the b-
Scheme 1. Synthesis of compounds 2–7.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2010, 10, 577–582
Difluorotetrahydropyridothiazinone
579
galactosidase (165 U/mg) from Fluka. For all experiments, 0.06 M
phosphate buffer (pH ¼ 6.0) was used except for the b-glucosi-
dase where an acetate buffer (0.05 M, pH ¼ 5.0) was applied.
Dilution factors of 6.0, 4.0, 3.0, 2.0, 1.0, 0.03, and 0.01 mg/mL
were applied for the inhibitor and 1.0, 0.5, 0.1, 0.05, and
0.025 mM for the 4-nitrophenol. UV-measurement was per-
formed at l ¼ 415 nm; experiments were performed at least
in triplicate, resulting in a SD of 0.0187 and R2 ¼ 0.99989.
From 2: A solution of 2 (670 mg, 2.20 mmol) in dry methanol
(40 mL) containing palladium on charcoal (10%; 700 mg) was
hydrogenated (508C, 5.14 atm, 48 h). The solution was filtered
through a pad of Celite. The filtrate was dried (MgSO4), the
solvent removed, and the residue was subjected to chromatog-
raphy (silica gel, methanol/ethyl acetate, 10:90) to yield 3
(443 mg, 94.0%) as
a
white solid; m. p.: 190–1918C;
[a]D ¼ ꢀ33.208 (c ¼ 1.0, MeOH); Rf (methanol/ethyl acetate,
10:90): 0.54; IR (KBr) n: 3472s, 2949s, 1636m, 1455m, 1410m,
1386m, 1353m, 1327m, 1255s, 1225s, 1121s, 1072s, 1029s, 982s,
Synthesis
Methyl-3-O-benzyl-2-deoxy-2,2-difluoro-b-D-arabino-
hexopyranoside 2
898m, 860s, 785m, 706m, 628m, 530m, 503m, 453w cmꢀ1; 1H-NMR
3
0
(500 MHz, CD3OD): d ¼ 4.54 (d, 1 H, J1,F ¼ 15.2 Hz, H-1), 3.89
3
2
(dd, 1H, J6B,5 ¼ 2.3, J6B,6A ¼ 12.1 Hz, H-6B), 3.68 (dd, 1H,
2
3
3J6A 5
,
¼ 5.8, J6A 6B
,
¼ 12.1 Hz, H-6A), 3.65 (ddd, 1H, J3,F’’ ¼ 3.8,
To a solution of 1 (1.05 g, 2.68 mmol) in dichloromethane
(19.6 mL) and water (0.4 mL), trifluoroacetic acid in dichloro-
methane (30%; 12.0 mL) was added dropwise and the solution
was stirred at 258C for 5 h. After the solution was diluted with
dichloromethane (70 mL) and washed with water (50 mL), the
organic and aqueous phases were separated and the aqueous
phase was extracted with dichloromethane (3 ꢁ 100 mL). The
combined organic phases were dried (Na2SO4), the solvent was
removed under diminished pressure and the residue subjected to
chromatography (silica gel, hexane/ethyl acetate, 5:50) to afford
2 (2.20 mmol, 82.3%) as a white solid; m. p.: 100–1018C;
[a]D ¼ ꢀ77.608 (c ¼ 0.44, CHCl3); Rf (hexane/ethyl acetate, 5:3):
0.12; IR (KBr) n: 3569s, 3489s, 3035m, 2942s, 2875m, 1959m,
1739m, 1661m, 1572m, 1499m, 1454s, 1404m, 1368m, 1347m,
1318m, 1249s, 1228s, 1091s, 1064s, 1046s, 1002s, 916m, 864s,
3J3,4 ¼ 9.3, 3J3,F’’ ¼ 19.5 Hz, H-3), 3.57 (s, 3H, OCH3), 3.45 (ddd, 1H,
3
3
3J4,F’’ ¼ 1.9, J4,5 ¼ 9.5, J4,3 ¼ 9.3 Hz, H-4), 3.36 (ddd, 1H,
3
3
3J5,6B ¼ 2.3, J5,4 ¼ 9.5, J5,6A ¼ 5.8 Hz, H-5) ppm; 13C-NMR
1
1
(125 MHz, CD3OD) d: 117.0 (dd, J2,F ¼ 253.6, J2,F ¼ 253.6 Hz,
C2), 100.5 (dd, 2J1,F ¼ 19.2, 2J1,F ¼ 27.1 Hz, C1), 78.1 (C5), 75.3 (dd,
2
3
2J3,F ¼ 18.9, J3,F ¼ 18.9 Hz, C3), 70.4 (d, J4,F ¼ 7.3 Hz, C4), 62.4
(C6), 57.9 (OCH3) ppm; 19F-NMR (188 MHz, CD3OD) d: ꢀ124.21
3
3
2
0
(ddd, 1F, J4,F’’ ¼ 1.9, JF’’,3 ¼ 3.8, JF’’,F ¼ 245.7 Hz, F’’), -143.19
(ddd, 1F, 3JF ,1¼ 15.2, 3JF ,3 ¼ 19.5, 2JF’’,F ¼ 245.7 Hz, F0) ppm; MS
(ESI – MeOH) m/z (%): 237.3 [M þ Na]þ (100), 341.1 [M3 þ K, H]2þ
(82), 447.9 [M4 þ K, H]2þ (28), 450.9 [M2 þ Na]þ (52). Anal. calcd.
for C7H12F2O5 (214.17): C, 39.26; H, 5.56. Found: C, 39.14; H, 5.79.
0
0
0
Methyl-2-deoxy-2,2-difluoro-6-O-trityl-b-D-arabino-
hexopyranoside 4
782s, 751m, 698s, 648m, 630m, 544m, 483m, 424m cmꢀ1
;
1H-
NMR (500 MHz, CDCl3) d: 7.37–7.30 (m, 5H, Ph), 5.00 (d, 1H,
2
2
To a solution of 3 (3.10 g, 14.48 mmol) and DMAP (1.00 g,
8.19 mmol) in dry pyridine (70 mL), trityl chloride (8.07 g,
28.95 mmol) was added in several portions and stirring was
continued at 408C for four days. The solvents were removed
under reduced pressure and the residue was dissolved in
dichloromethane (200 mL). The organic phase was washed with
water (150 mL) and the aqueous phase was extracted with
dichloromethane (3 ꢁ 100 mL). The combined organic phases
were dried (MgSO4) and the solvent was removed under reduced
pressure. The crude product 4 was directly used in the next step;
Rf (hexane/ethyl acetate, 50:50): 0.48.
0
0
JH’’,H ¼ 11.5 Hz, CH’’2, OBn), 4.66 (d, 1H, JH ,H’’ ¼ 11.5 Hz,
3
CH02, OBn), 4.44 (d, 1H, J1,F ¼ 14.6 Hz, H-1), 3.91 (dd, 1H,
0
3J6B,5 ¼ 3.4, J6B,6A ¼ 12.0 Hz, H-6B), 3.80 (dd, 1H, J6A,5 ¼ 4.7,
2
3
2J6A 6B
,
¼ 12.0 Hz, H-6A), 3.76 (ddd, 1H, J4,F ¼ 2.1, J4,5 ¼ 9.5,
3
3
0
3J4,3 ¼ 9.3 Hz, H-4), 3.62 (s, 3H, OCH3), 3.55 (ddd, 1H,
3
3
3
0
J3,F ¼ 5.1, J3,4 ¼ 9.3, J3,F ¼ 19.5 Hz, H-3), 3.40 (ddd, 1H,
3J5,6B ¼ 3.4, J5,4 ¼ 9.5, J5,6A ¼ 4.7 Hz, H-5) ppm; 13C-NMR
3
3
(125 MHz, CDCl3) d: 137.1 (Car), 128.8 (Car), 128.7 (Car), 128.5
1
(Car), 128.4 (Car), 128.3 (Car), 116.1 (dd, J2,F ¼ 253.9,
1J2,F ¼ 258.2 Hz, C2), 99.4 (dd, J1,F ¼ 19.2, J1,F ¼ 8.7 Hz, C1),
2
2
2
2
80.6 (dd, J3,F ¼ 18.2, J3,F ¼ 18.2 Hz, C3), 75.2 (C5), 75.0 (d,
4JCH2(OBn),F ¼ 3.4 Hz, CH2, OBn), 69.0 (d, J4,F ¼ 8.2 Hz, C4), 62.1
3
(C6), 58.1 (OCH3) ppm; 19F-NMR (188 MHz, CDCl3) d: ꢀ118.82 (dd,
Methyl-2-deoxy-2,2-difluoro-3,4-di-O-pivaloyl-6-O-trityl-b-
D-arabino-hexopyranoside 5
3
2
0
1F, JF’’,3 ¼ 5.1, JF’’,F ¼ 249.0 Hz, F’’), -138.37 (dddd, 1F,
JF ,4 ¼ 2.1, JF ,1 ¼ 14.6, JF ,3 ¼ 19.5, JF ,F’’ ¼ 249.0 Hz, F0) ppm;
4
3
3
2
0
0
0
0
To an ice-cold solution of 4 (4.77 g, 10.45 mmol) in pyridine
(50 mL), pivaloyl chloride (3.21 mL, 26.13 mmol) was added
dropwise, the solution was allowed to warm to 258C and was
stirred at this temperature for 24 h, followed by stirring at 508C
for another 24 h. The solvent was removed under reduced pres-
sure and the remaining residue was subjected to chromatog-
raphy (silica gel, hexane/ethyl acetate, 85:15) to afford 5 (4.84 g,
74.1%) as a white solid; m. p.: 53–548C; [a]D ¼ ꢀ1.538 (c ¼ 0.46,
CHCl3); Rf (hexane/ethyl acetate, 85:15): 0.47; IR (KBr) n: 3455m,
3061s, 3021s, 2981s, 2943s, 2916s, 2873s, 1966m, 1753s, 1736s,
1596m, 1481s, 1449s, 1399s, 1369s, 1322s, 1281s, 1214s, 1144s,
1064s, 1035s, 1011s, 987s, 938m, 899m, 889m, 859s, 807m, 778s,
764s, 710s, 699s, 671m, 645m, 634s, 592w, 568m, 556m, 544m,
MS (ESI – MeOH) m/z (%): 305.2 [M þ H]þ (15), 322.2 [M þ NH4]þ
(75), 327.3 [M þ Na]þ (100), 630.8 [M2 þ Na]þ (95); MS (ESI –
MeOH þ LiClO4) m/z (%): 331.3 [M þ Li]þ (100), 342.7 [M þ Li,
MeOH]þ (15), 614.9 [M2 þ Li]þ (5). Anal. calcd. for C14H18F2O5
(304.29): C, 55.26; H, 5.96. Found: C, 55.14; H, 6.17.
Methyl-2-deoxy-2,2-difluoro-b-D-arabino-
hexopyranoside 3
From 1: A solution of 1 (550 mg, 1.40 mmol) in dry methanol
(30 mL) containing palladium on charcoal (10%; 600 mg) was
hydrogenated (508C, 5.14 atm) for 24 h; additional palladium on
charcoal (10%; 500 mg) was added and hydrogenation (508C, 5.14
atm) continued for another 24 h. The solution was filtered
through a pad of Celite. The filtrate was dried (MgSO4), the
solvent removed, and the residue was subjected to chromatog-
raphy (silica gel, methanol/ethyl acetate, 10:90) to afford 3
(290 mg, 96.5%) as a white solid.
531m, 514m, 482w, 459m cmꢀ1 1H-NMR (500 MHz, CDCl3) d:
;
7.46–7.44 (m, 5H, Ph), 7.29–7.20 (m, 10 H, Ph), 5.29 (ddd, 1H,
3
3
3
0
J3,F’’ ¼ 5.1, J3,4 ¼ 9.9, J3,F ¼ 19. z, H-3), 5.17 (ddd, 1H,
3
3
3
0
J4,F ¼ 1.0, J4,3 ¼ 9.9, J4,5 ¼ 10.0 Hz, H-4), 4.60 (d, 1H,
3J1,F ¼ 14.1 Hz, H-1), 3.75 (ddd, 1H, J5,6B ¼ 6.5, J5,4 ¼ 10.0,
3
3
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

580
R. Csuk and E. Prell
Arch. Pharm. Chem. Life Sci. 2010, 10, 577–582
3J5,6A ¼ 1.8 Hz, H-5), 3.74 (s, 3H, OCH3), 3.24 (dd, 1H, 3J6B,5 ¼ 6.5,
The remaining residue was subjected to chromatography (silica
gel, hexane/ethyl acetate, 85:15) to afford 7 (698 mg, 98.2%) as a
white solid; m. p.: 160–1638C; [a]D ¼ ꢀ1.898 (c ¼ 0.32, CHCl3); Rf
(hexane/ethyl acetate, 85:15): 0.39; IR (KBr) n: 3449m, 2972m,
2946m, 1746s, 1733s, 1630w, 1482m, 1461m, 1400m, 1372m,
1281m, 1232m, 1148s, 1068s, 1033m, 1007m, 981w, 962w,
2J6B,6A ¼ 10.4 Hz,
H-6B),
3.10
(dd,
1H,
3J6A 5
,
¼ 1.8,
2J6A 6B
,
¼ 10.4 Hz, H-6A), 1.18 (s, 9H, CH3, OPiv), 0.86 (s, 9H,
13
–
3
CH3, OPiv) ppm; C-NMR (125 MHz, CDCl ) d: 176.9 (C O,
–
–
–
OPiv), 176.7 (C O, OPiv), 143.4 (Ci-ar, trityl), 128.6 (Car), 127.8
1
1
(Car), 127.0 (Car), 114.3 (dd, J2,F ¼ 257.1, J2,F ¼ 257.1 Hz, C2),
99.2 (dd, 2J1,F ¼ 18.4, 2J1,F ¼ 26.5 Hz, C1), 86.7 (CPh3 (trityl)), 74.2
901w, 860m, 798w, 770w, 686w, 652w, 562w, 536w, 502w, 473w
3
2
2
(C5), 70.9 (dd, J3,F ¼ 21.5, J3,F ¼ 18.0 Hz, C3), 67.3 (d,
4J4,F ¼ 6.5 Hz, C4), 62.2 (C6), 57.5 (OCH3), 39.1 (C(CH3)3, OPiv),
38.5 (C(CH3)3, OPiv), 27.1 (CH3, OPiv), 26.9 (CH3, OPiv) ppm; 19F-
cmꢀ1
;
1H-NMR (500 MHz, CDCl3) d: 5.34 (ddd, 1H, J3,F’’ ¼ 5.1,
3
3
3
0
0
J3,4 ¼ 9.6, J3,F ¼ 19.1 Hz, H-3), 5.13 (ddd, 1H, J4,F ¼ 1.1,
3J4,3 ¼ 9.6, J4,5 ¼ 9.6 Hz, H-4), 4.57 (d, 1H, J1,F ¼ 13.7 Hz, H-1),
3
3
3
3
3
NMR (188 MHz, CDCl3) d: ꢀ122.29 (dd, 1F, JF’’,3 ¼ 5.1,
3.81 (dt, 1H, J5,(6B,6A) ¼ 5.2, J5,4 ¼ 9.6 Hz, H-5), 3.67 (s, 3H,
2
3
4
3
0
0
JF’’,F ¼ 247.4 Hz, F’’), ꢀ137.75 (dddd, 1F,
JF ,4 ¼ 1.0,
OCH3), 3.40 (d, 2H, J(6B,6A),5 ¼ 5.2 Hz, H-6B, H-6A), 1.20 (s, 9H,
3
2
JF ,1 ¼ 14.1, JF ,3 ¼ 19.7, JF’’,F ¼ 247.4 Hz, F0) ppm; MS (ESI –
CH3, OPiv), 1.17 (s, 9H, CH3, OPiv) ppm; 13C-NMR (125 MHz, CDCl3)
0
0
0
MeOH) m/z (%): 243.3 (trityl, 30), 642.0 [M þ NH4]þ (23), 647.3
[M þ Na]þ (100), 1270.5 [M2 þ Na]þ (16). Anal. calcd. for
C36H42F2O7 (624.73): C, 69.21; H, 6.78. Found: C, 68.98; H, 6.91.
d: 176.9 (C O, OPiv), 176.4 (C O, OPiv), 113.9 (dd, J2,F ¼ 255.0,
1
–
–
–
–
1J2,F ¼ 257.7 Hz, C2), 99.0 (dd, J1,F ¼ 19.4, J1,F ¼ 27.4 Hz, C1),
2
2
2
2
74.0 (C5), 70.2 (dd, J3,F ¼ 18.5, J3,F ¼ 22.1 Hz, C3), 69.4 (d,
3J4,F ¼ 6.8 Hz, C4), 57.96 (OCH3), 39.0 (C(CH3)3, OPiv), 38.8
(C(CH3)3, OPiv), 29.9 (C6), 27.0 (CH3, OPiv), 26.9 (CH3, OPiv)
ppm; 19F-NMR (188 MHz, CDCl3) d: ꢀ122.80 (dd, 1F,
Methyl-2-deoxy-2,2-difluoro-3,4-di-O-pivaloyl-b-D-
arabino-hexopyranoside 6
3
3
2
4
0
0
JF’’,3 ¼ 5.1, JF’’,F ¼ 249.0 Hz, F’’), ꢀ137.3 (dddd, 1F, JF ,4 ¼ 1.1,
To an ice-cold solution of 5 (1.00 g, 1.60 mmol) in anhydrous
dichloromethane (20 mL), trimethylsilyl iodide (858 mL,
6.00 mmol) was added dropwise and stirring was continued at
this temperature for 30 min followed by stirring at 258C for 12 h.
Water (10 mL) was added and the solution was stirred at 258C for
10 min. Dichloromethane (80 mL) was added and the solution
was washed with aqueous sodium thiosulfate (10%, 50 mL). The
aq. phase was extracted with dichloromethane (3 ꢁ 100 mL) and
the combined organic layers were dried (MgSO4). The solvent was
removed under diminished pressure and the remaining residue
subjected to chromatography (silica gel, hexane/ethyl acetate,
50:50) to afford 6 (610 mg, 99.7%) as a white solid; m. p.: 160–
1628C; [a]D ¼ ꢀ5.548 (c ¼ 0.46, CHCl3); Rf (hexane/ethyl acetate,
50:50): 0.65; IR (KBr) n: 3386s, 2978s, 2876m, 1747s, 1725s, 1482m,
1463m, 1399m, 1372m, 1279m, 1228m, 1147s, 1103s, 1087s,
1045s, 1001m, 941w, 911m, 894w, 860m, 810w, 766w, 750w,
3
2
JF ,1 ¼ 13.7, JF ,3 ¼ 19.1, JF’’,F ¼ 249.0 Hz, F0) ppm; MS (ESI –
0
0
0
MeOH) m/z (%): 445.1 and 447.1 [M þ H]þ (10 each), 462.2 and
464.2 [M þ NH4]þ (50 each), 467.2 and 469.1 [M þ Na]þ (60 each),
685.9 [MA3 þ K, H]2þ (6), 910.6 [M2 þ Na]þ (58), 912.5
[MA þ MB þ Na]þ (100), 914.5 [M2 þ Na]þ (54). Anal. calcd. for
C17H27BrF2O6 (445.30): C, 45.85; H, 6.11. Found: C, 45.68; H, 6.17.
Methyl-6-bromo-2,6-dideoxy-2,2-difluoro-3,4-di-O-
pivaloyl-D-arabino-hex-5-ulosonate 8
A solution of acetic acid (19.0 mL) and acetic anhydride
(2.0 mL) under argon was stirred at 508C for 2 h and cooled
to 258C. To a solution of 7 (698 mg, 1.57 mmol) the above
described solution was added at 258C and the mixture was
stirred at this temperature for 10 min. Then, chromium(VI)
oxide (1.09 g, 10.91 mmol) was added and the suspension was
stirred at 258C for two hours. The solution was filtered
through a thin layer of silica gel and diluted with ethyl
acetate (3 ꢁ 100 mL). The combined organic layers were dried
(Na2SO4), the solvent was removed under reduced pressure
and the remaining residue was subjected to chromatography
(silica gel, hexane/ethyl acetate, 85:15) to afford 8 (490 mg,
68.1%) as a colorless oil; [a]D ¼ þ18.938 (c ¼ 0.48, CHCl3); Rf
(hexane/ethyl acetate, 85:15): 0.44; IR (KBr) n: 2977m, 2876m,
1749s, 1482m, 1462m, 1399m, 1368m, 1275m, 1230m, 1121s,
663w, 588w, 542m, 450w cmꢀ1
;
1H-NMR (500 MHz, CDCl3) d:
3
3
3
0
5.40 (ddd, 1H, J3,F’’ ¼ 5.0, J3,4 ¼ 10.0, J3,F ¼ 19.6 Hz, H-3),
3
3
3
0
5.17 (ddd, 1H, J4,F ¼ 1.1, J4,3 ¼ 10.0, J4,5 ¼ 9.8 Hz, H-4), 4.57
(d, 1H, 3J1,F ¼ 14.1 Hz, H-1), 3.64 (s, 3H, OCH3), 3.75 (m, 1H, H-6B),
0
3.62-3.56 (m, 2H, H-5, H-6A), 1.21 (s, 9H, CH3, OPiv), 1.16 (s, 9H,
–
CH3, OPiv) ppm; 13C-NMR (125 MHz, CDCl ) d: 177.3 (C O, OPiv),
–
3
1
1
–
–
177.1 (C O, OPiv), 114.1 (dd, J ¼ 257.6, J2,F ¼ 254.7 Hz, C2),
2,F
2
2
99.2 (dd, J1,F ¼ 19.2, J1,F ¼ 26.9 Hz, C1), 74.4 (C5), 70.4 (dd,
2J3,F ¼ 18.2, J3,F ¼ 21.5 Hz, C3), 67.1 (C4), 61.1 (C6), 58.1
2
(OCH3), 39.0 (C(CH3)3, OPiv), 38.8 (C(CH3)3, OPiv), 27.0 (CH3,
OPiv), 26.9 (CH3, OPiv) ppm; 19F-NMR (188 MHz, CDCl3) d:
1038m, 941m, 805m, 765m, 522w cmꢀ1
;
1H-NMR (500 MHz,
3
CDCl3) d: 5.87 (d, 1H, J4,3 ¼ 1.6 Hz, H-4), 5.75 (ddd, 1H,
ꢀ122.28 (dd, 1F, 3JF’’,3 ¼ 5.0, 2JF’’,F ¼ 248.5 Hz, F’’), -137.81 (dddd,
0
3
3
3
0
J3,F’’ ¼ 6.8, J3,4 ¼ 1.6, J3,F ¼ 16.7 Hz, H-3), 4.08 (d, 1H,
4
3
3
2
1F, JF ,4 ¼ 1.1, JF ,1 ¼ 14.1, JF ,3 ¼ 19.6, JF’’,F ¼ 248.5 Hz, F0)
ppm; MS (ESI – MeOH) m/z (%): 383.3 [M þ H]þ (9), 400.3
[M þ NH4]þ (52), 405.3 [M þ Na]þ (27), 593.0 [M3 þ K, H]2þ (8),
786.9 [M2 þ Na]þ (100). Anal. calcd. for C17H28F2O7 (382.41): C,
53.40; H, 7.38. Found: C, 53.29; H, 7.52.
0
0
0
0
2J6B,6A ¼ 13.4 Hz, H-6B), 4.02 (d, 1H, J6A 6B
¼ 13.4 Hz, H-6A),
13
,
3.88 (s, 3H, COOCH3), 1.26 (s, 9H, CH3, OPiv), 1.18 (s, 9H, CH3,
2
–
–
OPiv) ppm; C-NMR (125 MHz, CDCl ) d: 194.7 (C O (C5)),
3
2
–
–
–
–
176.7 (C O, OPiv), 176.5 (C O, OPiv), 162.2 (dd, JC,F ¼ 30.2,
2JC,F ¼ 32.7 Hz,
C
O
(COOCH3)), 112.0 (dd, J2,F ¼ 255.3,
2
1
–
–
1J2,F ¼ 262.0 Hz, C2), 71.1 (C4), 69.1 (dd, J3,F ¼ 23.0,
2J3,F ¼ 30.8 Hz, C3), 53.9 (COOCH3), 38.9 (C(CH3)3, OPiv), 38.8
(C(CH3)3, OPiv), 30.8 (C6), 26.8 (CH3, OPiv), 26.8 (CH3, OPiv)
ppm; 19F-NMR (188 MHz, CDCl3) d: ꢀ111.16 (dd, 1F,
Methyl-6-bromo-2,6-dideoxy-2,2-difluoro-3,4-di-O-
pivaloyl-b-D-arabino-hexopyranoside 7
To an ice-cold solution of 6 (610 mg, 1.60 mmol) in pyridine
(10 mL), triphenylphosphane (837 mg, 3.19 mmol) and CBr4
(794 mg, 2.39 mmol) were slowly added and the solution was
stirred at 08C for 10 min followed by stirring at 658C for another
4 h. The solution was cooled to 258C, methanol (10 mL) was
added and the solvents were removed under reduced pressure.
3JF’’,3 ¼ 6.8,
JF’’,F ¼ 270.4 Hz, F’’), ꢀ118.04 (dd, 1F,
2
0
3
2
JF ,3 ¼ 16.7, JF’’,F ¼ 270.4 Hz, F0) ppm; MS (ESI – MeOH) m/z
(%): 459.1 and 461.1 [M þ H]þ (20 each), 476.2 and 478.1
[M þ NH4]þ (40 each), 481.2 and 483.1 [M þ Na]þ (90 each),
508.0 and 510.0 [M þ NH4, MeOH]þ (40 each), 513.1 and 515.1
0
0
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2010, 10, 577–582
Difluorotetrahydropyridothiazinone
581
2
[M þ Na, MeOH]þ (89 each), 708.9 [MA2 þ MB þ K, H]2þ (15),
938.5 [MA2 þ Na]þ (55), 940.5 [MA þ MB þ Na]þ (100), 942.5
[MB2 þ Na]þ (55). Anal. calcd. for C17H25BrF2O7 (459.29): C,
44.46; H, 5.49. Found: C, 44.31, H, 5.64.
1a0), 3.11 (d, 1H, J6B,6A ¼ 13.7 Hz, H-6b00), 2.92 (d, 1H,
2J6B,6A ¼ 14.0 Hz, H-6a00), 2.82 (ddd, 1H,
J2b ,1b ¼ 4.3,
3
00
0
3
2
00
00
00
0
J2b ,1b ¼ 2.6,
J2b ,2b ¼ 13.7 Hz, H-2b00), 2.78 (ddd, 1H,
3
3
2
J2b ,1b ¼ 5.4, J2b ,1b ¼ 1.9, J2b ,2b ¼ 13.7 Hz, ethylene-H-2b0),
0
0
0
00
0
00
3
3
2
00
0
00
00
00
0
2.75 (ddd, 1H, J2a ,1a ¼ 3.1, J2a ,1a ¼ 3.0, J2a ,2a ¼ 13.8 Hz,
3
3
ethylene-H-2a00), 2.65 (ddd, 1H, J2a ,1a ¼ 1.6, J2a ,1a ¼ 3.0,
0
0
0
00
(8S, 9R)-7,7-Difluoro-6-oxo-3,4,6,7,8,9-
J2a ,2a ¼ 13.8 Hz, H-2a0), 2.57 (dd, 1H, 3J6B H
,
¼ 2.1,
¼ 1.9,
2
0
00
hexahydropyrido[2.1-c][1,4]thiazine-8,9-diylbis(2,2-
dimethylpropanoate) 9, (8S, 9S, 9aR,S)-7,7-difluoro-9a-
hydroxy-6-oxo-octahydropyrido[2.1-c][1,4]thiazine-8,9-
diyl-bis(2,2-dimethylpropanoate) 10, and (8S)-7,7-difluoro-
6-oxo-1,3,4,6,7,8-hexahydropyrido[2.1-c][1,4]thiazine-8,9-
2J6B,6A ¼ 14.0 Hz, H-6a00),
2.45
(dd,
1H,
3J6B H
,
2J6B,6A ¼ 13.7 Hz, H-6b00), 1.22 (s, 9H, CH3, OPiv), 1.21 (s, 9H,
CH3, OPiv), 1.21 (s, 9H, CH3, OPiv), 1.20 (s, 9H, CH3, OPiv) ppm;
–
13
–
–
C-NMR (125 MHz, CDCl ) d: 176.9 (C O, OPiv), 176.7 (C O, OPiv),
–
3
2
–
–
–
–
176.5 (C O, OPiv), 175.9 (C O, OPiv), 161.5 (dd, JC,F ¼ 28.7,
JC,F ¼ 26.3 Hz, C O (CONR)b), 109.7 (dd, 1J2,F ¼ 246.6,
2
–
–
diylbis(2,2-dimethylpropanoate) 11
1J2,F ¼ 252.3 Hz, C2a), 109.6 (dd, J2,F ¼ 246.6, J2,F ¼ 252.3 Hz,
1
1
To a solution of 8 (1.55 g, 3.38 mmol) in absolute methanol
(60 mL), 2-aminoethanethiol (318 mg, 4.12 mmol) was added
and the solution was stirred at 258C for 24 h. The solvent was
removed under reduced pressure and the remaining residue
subjected to chromatography (silica gel, hexane/ethyl acetate,
5:3) to afford 9 (590 mg, 41.3%), 10 (340 mg, 23.8%), and 11
(260 mg, 18.2%).
2
C2b), 82.2 (C5b), 80.9 (C5a), 68.6 (d, J4,F ¼ 9.6 Hz, C4a), 68.3 (d,
2J4,F ¼ 9.5 Hz, C4b), 66.4 (dd, J3,F ¼ 16.8, J3,F ¼ 23.5 Hz, C3a),
66.1 (dd, 2J3,F ¼ 16.8, 2J3,F ¼ 23.5 Hz, C3b), 40.0 (C10a), 39.5 (C10b),
39.1 (C(CH3)3, OPiv), 39.1 (C(CH3)3, OPiv), 39.0 (C(CH3)3, OPiv), 39.0
(C(CH3)3, OPiv), 37.3 (C6a), 36.0 (C6b), 27.1 (CH3, OPiv), 27.0 (CH3,
2
2
OPiv), 26.9 (CH3, OPiv), 26.9 (CH3, OPiv), 26.6 (C20), 26.3 (C20) ppm;
19F-NMR (188 MHz, CDCl3) d: ꢀ111.54 (dd, 1F, JF ,3 ¼ 17.2,
3
00
2
2
2
2
3
JF ,F ¼ 281.8 Hz, Fa00), ꢀ111.12 (dd, 1F,
JF ,3 ¼ 15.4,
00
0
00
3
JF ,F ¼ 299.1 Hz, Fb00), ꢀ114.79 (dd, 1F,
JF ,3 ¼ 6.3,
Data for compound 9
00
0
0
3
JF ,F ¼ 281.8 Hz, Fa0), ꢀ113.99 (dd, 1F,
JF ,3 ¼ 6.2,
00
0
0
White solid; m. p.: 167–1688C; [a]D ¼ ꢀ14.36 8 (c ¼ 0.36, CHCl3);
Rf (hexane/ethyl acetate, 5:3): 0.78; IR (KBr) n: 3467s, 2973s, 2934s,
2876s, 1752s, 1706s, 1630m, 1483s, 1458m, 1408s, 1372m, 1316m,
1279s, 1225s, 1196s, 1147s, 1073s, 1040s, 1013m, 991m, 932m,
903m, 892m, 878m, 859m, 838m, 821m, 795m, 770m, 759m, 747m,
706w, 678w, 577w, 545m, 532m, 501m, 479m, 441w cmꢀ1; 1H-NMR
JF ,F ¼ 299.1 Hz, Fb0) ppm; MS (ESI – MeOH) m/z (%): 424.0
00
0
[M þ H]þ (10), 441.3 [M þ NH4]þ (12), 446.2 [M þ Na]þ (36),
654.6 [M3 þ K, H]2þ (4), 868.9 [M2 þ Na]þ (100). Anal. calcd. for
C18H27F2O6NS (423.48): C, 51.05; H, 6.43; N, 3.31; S, 7.57. Found:
C, 50.93; H, 6.52; N, 3.25; S, 7.59.
3
(500 MHz, CDCl3) d: 5.79 (s, 1H, H-6), 5.56 (dd, 1H, J4,3 ¼ 5.6,
3
3
3J4,F’ ¼ 5.2 Hz, H-4), 5.42 (ddd, 1H, J3,F’’ ¼ 8.7, J3,4 ¼ 5.6,
Data for compound 11
3J3,F’ ¼ 6.8 Hz, H-3), 4.63 (ddd, 1H, J1’’,2’ ¼ 3.5, J1’’,2’’ ¼ 5.0,
2J1’’,1’ ¼ 13.5 Hz, H-1’’), 3.67 (m, 1H, H-1’), 3.05–3.02 (m, 2H, H-
2’’, H-2’), 1.21 (s, 9H, CH3, OPiv), 1.20 (s, 9H, CH3, OPiv) ppm; 13C-
3
3
White solid; m. p.: 257–2588C; [a]D ¼ ꢀ56.958 (c ¼ 0.43 g,
CHCl3); Rf (hexane/ethyl acetate, 5:3): 0.20; IR (KBr) n: 3429m,
2978m, 2934m, 2874m, 1744s, 1652m, 1561s, 1525m, 1480m,
1448m, 1420m, 1400m, 1336m, 1303m, 1276m, 1229m, 1211m,
1151s, 1057m, 1036m, 971m, 909m, 852m, 820w, 754m, 541m,
–
–
NMR (100 MHz, CDCl ) d: 176.5 (C O, OPiv), 175.7 (C O, OPiv),
–
–
3
2
2
–
157.7 (dd, JC,F ¼ 4.7, JC,F ¼ 4.3 Hz, C O (CONR)), 124.9 (C5),
–
1
1
108.8 (C6), 108.4 (dd, J2,F ¼ 249.3, J2,F ¼ 252.9 Hz, C2), 68.1
449w cmꢀ1; 1H-NMR (500 MHz, CDCl3) d: 5.72 (dd, 1H, J6B H
,
¼ 0.9,
2
2
(C4), 67.7 (dd, J3,F ¼ 19.5, J3,F ¼ 29.5 Hz, C3), 39.7 (C1’), 39.1
(C(CH3)3, OPiv), 39.1 (C(CH3)3, OPiv), 27.1 (CH3, OPiv), 27.1 (CH3,
OPiv), 27.0 (CH3, OPiv), 27.0 (CH3, OPiv), 26.9 (CH3, OPiv), 25.3 (C2’)
2J6B,6A ¼ 6.6 Hz, H-6B), 5.60 (m, 1H, H-6A), 5.55 (ddd, 1H,
3
3
3
00
0
J3,F ¼ 5.2, J3,4 ¼ 6.5, J3,F ¼ 13.8 Hz, H-3), 3.72–3.69 (m, 2H,
H-1B, H-10), 2.90–2.88 (m, 2H, H-200, H-20), 1.22 (s, 9H, CH3, OPiv),
ppm; 19F-NMR (188 MHz, CDCl3) d: ꢀ106.94 (dd, 1F, JF’’,3 ¼ 8.7,
3
1.19 (s, 9H, CH3, OPiv) ppm; 13C-NMR (125 MHz, CDCl3) d: 178.5
2JF’’,F’ ¼ 299.1 Hz, F’’), ꢀ114.79 (ddd, 1F, JF’,4 ¼ 5.2, JF’,3 ¼ 6.8,
2JF’’,F’ ¼ 299.1 Hz, F’) ppm; MS (ESI – MeOH) m/z (%): 423.1
[M þ NH4]þ (8), 428.1 [M þ Na]þ (100), 832.8 [M2 þ Na]þ (12).
Anal. calcd. for C18H25F2O5NS (405.46): C, 53.32; H, 6.22; N,
3.46; S, 7.91. Found: C, 53.08; H, 6.32; N, 3.39; S, 7.79.
4
3
2
–
–
–
–
(C O, OPiv), 176.3 (C O, OPiv), 176.0 (dd, JC,F ¼ 19.0,
2JC,F ¼ 19.0 Hz, CONR), 149.3 (C5), 109.6 (dd, J2,F ¼ 251.4,
1
1J2,F ¼ 251.8 Hz, C2), 100.9 (C4), 69.6 (dd, J3,F ¼ 21.1,
2
2J3,F ¼ 26.9 Hz, C3), 68.4 (C6), 43.7 (C10), 39.3 (C(CH3)3, OPiv),
39.1 (C(CH3)3, OPiv), 27.1 (CH3, OPiv), 27.0 (CH3, OPiv), 23.0 (C20)
ppm; 19F-NMR (188 MHz, CDCl3) d: ꢀ115.18 (dd, 1F, JF ,3 ¼ 5.2,
3
00
2
2
3
JF ,F ¼ 280.0 Hz, F00), ꢀ117.95 (dd, 1F,
JF ,3 ¼ 13.8,
Data for compound 10
00
0
0
JF ,F ¼ 280.0 Hz, F0) ppm; MS (ESI – MeOH) m/z (%): 406.2
White solid; m. p.: 132–1338C; [a]D ¼ ꢀ38.498 (c ¼ 0.49, CHCl3);
Rf (hexane/ethyl acetate, 5:3): 0.55; IR (KBr) n: 3424m, 2974m,
2937m, 2876m, 1751s, 1684s, 1483m, 1462m, 1433m, 1399m,
1372m, 1278m, 1233m, 1148s, 1122s, 1064m, 1043m, 1007m,
980m, 944w, 1064m, 1043m, 1007m, 980m, 944w, 894m, 879w,
864w, 836w, 822w, 796w, 758w, 540m, 520w, 464w cmꢀ1; 1H-NMR
00
0
[M þ H]þ (35), 428.2 [M þ Na]þ (50), 627.6 [M3 þ K, H]2þ (3),
832.9 [M2 þ Na]þ (100); MS (ESI – MeOH) m/z (%): 404.6 [M –
H]ꢀ (100). Anal. calcd. for C18H25F2O5NS (405.46): C, 53.32; H,
6.22; N, 3.46; S, 7.91. Found: C, 53.21; H, 6.41; N, 3.28; S, 7.78.
3
3
00
(500 MHz, CDCl3) d: 5.86 (ddd, 1H, J3,F ¼ 17.2, J3,4 ¼ 11.0,
3
3
(8S, 9R)-7,7-Difluoro-8,9-dihydroxy-3,4,8,9-
tetrahydropyrido[2.1-c][1,4]thiazine-6(7H)-one 12
To a solution of 9 (200 mg, 0.49 mmol) in absolute methanol
(20 mL), sodium methoxide (30 mg, 0.56 mmol) was added in
small portions and the solution was stirred for 4 h at 258C. The
solvent was evaporated under reduced pressure and the remain-
ing residue was subjected to chromatography (silica gel,
0
J3,F ¼ 6.3 Hz, H-3a), 5.71 (d, 1 H, J4,3 ¼ 11.3 Hz, H-4b), 5.50
3
3
3
00
0
(ddd, 1H, J3,F ¼ 15.4, J3,4 ¼ 11.3, J3,F ¼ 6.2 Hz, H-3b), 5.45
3
3
00
0
(d, 1H, J4,3 ¼ 11.0 Hz, H-4a), 4.72 (ddd, 1H, J1b ,2b ¼ 2.6,
3
2
J1b ,2b ¼ 5.4,
J1b ,1b ¼ 14.4 Hz, H-1b00), 4.58 (ddd, 1H,
00
00
00
0
3
3
2
J1a ,2a ¼ 3.0, J1a ,2a ¼ 3.0, J1a ,1a ¼ 14.4 Hz, H-1a00), 3.48
00
0
00
00
00
0
3
3
2
(ddd, 1H, J1b ,2b ¼ 1.9, J1b ,2b ¼ 4.3, J1b ,1b ¼ 14.4 Hz, H-1b0),
0
0
0
00
0
00
3
3
2
0
0
0
00
0
00
3.27 (ddd, 1H, J1a ,2a ¼ 1.6, J1a ,2a ¼ 3.1, J1a ,1a ¼ 14.3 Hz, H-
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

582
R. Csuk and E. Prell
Arch. Pharm. Chem. Life Sci. 2010, 10, 577–582
methanol/ethyl acetate, 20:80) to afford 12 (110 mg, 94.0%) as a
white solid; m. p.: >2508C (decomposition); [a]D ¼ ꢀ75.008
(c ¼ 0.18, MeOH); Rf (hexane/ethyl acetate, 50:50): 0.33; IR
(Film) n: 3387m, 3314m, 3080w, 1664s, 1614m, 1425m, 1404m,
1369m, 1348m, 1277w, 1256w, 1209w, 1192w, 1157w, 1142w,
1132w, 1090w, 1065m, 1051m, 1020m, 999m, 906w, 879m,
[8] E. Prell, R. Csuk, Bioorg. Med. Chem. Lett. 2009, 19, 5673–
5674.
[9] H. Huang, D. A. Hutta, J. M. Rinker, H. Hu, et al., J. Med. Chem.
2009, 52, 1081–1099.
[10] P. D. Pierson, A. Fettes, C. Freichel, S. Gatti-McArthur, et al.,
J. Med. Chem. 2009, 52, 3855–3868.
839m, 825w, 812m, 793w, 748w cmꢀ1
;
1H-NMR (500 MHz,
3
[11] P. D. Pierson, C. Freichel, S. Gatti-MacArthur, C. Hertel, et al.,
Chimia: Int. J. Chem. 2009, 63, 275–278.
00
CD3OD) d: 5.90 (s, 1H, H-6), 4.27 (ddd, 1H, J4,F ¼ 0.9,
3
3
3
3
0
00
0
J4,3 ¼ 3.8, J4,F ¼ 8.0 Hz, H-4), 4.22 (ddd, 1H, J1 ,2 ¼ 3.8,
2
J1 ,2 ¼ 5.9, J1 ,1 ¼ 13.5 Hz, H-100), 3.94–3.88 (m, 2H, H-3, H-
[12] A. El-Laghdach, R. Echarri, M. I. Matheu, M. I. Barrena, et al.,
J. Org. Chem. 1991, 56, 4556–4559.
00 00
00
0
10), 3.03 (m, 2H, H-200, H-20) ppm; 13C-NMR (125 MHz, CD3OD) d:
2
2
159.4 (dd, JC,F ¼ 29.8, JC,F ¼ 29.7 Hz, CONR), 129.3 (C5), 111.0
[13] P. V. Murphy, J. L. O’Brien, L. J. Gorey-Feret, A. B. I. Smith,
Tetrahedron 2003, 59, 2259–2271.
1
1
(dd, J2,F ¼ 245.7, J2,F ¼ 249.5 Hz, C2), 103.9 (C6), 70.9 (dd,
2J4,F ¼ 19.7, 2J4,F ¼ 23.0 Hz, C3), 69.5 (dd, 2J3,F ¼ 2.9,
2J3,F ¼ 5.8 Hz, C4), 39.7 (C10), 24.2 (C20) ppm; 19F-NMR
[14] A. E. Martell, R. M. Herbst, J. Org. Chem. 1941, 6, 878–
887.
3
3
00
00
(188 MHz, CDCl3) d: ꢀ110.68 (ddd, 1F, JF ,4 ¼ 0.9, JF ,3 ¼ 9.1,
[15] T. H. Bevan, T. Martin, J. M. Tiplady, J. Chem. Soc. 1957, 3086–
3089.
2
4
JF ,F ¼ 290.6 Hz, F00), ꢀ116.05 (ddd, 1F, JF ,4 ¼ 8.0, 3JF ,3 ¼ 11.7,
00
0
0
0
2
JF ,F ¼ 290.6 Hz, F0) ppm; MS (ESI – MeOH) m/z (%): 238.4
00
0
[M þ H]þ (8), 255.2 [M þ NH4]þ (49), 260.2 [M þ Na]þ (92),
291.8 [M þ Na, MeOH]þ (100), 493.9 [M4 þ K, H]þ (10), 496.8
[M2 þ Na]þ (18). Anal. calcd. for C8H9F2SNO3 (237.22): C, 40.51;
H, 3.82; N, 5.90; S, 13.52. Found: C, 40.39; H, 3.95; N, 5.85; S, 13.67.
[16] P. T. Gilham, H. G. Khorana, J. Am. Chem. Soc. 1959, 81, 4647–
4650.
[17] R. C. Bernotas, M. A. Pezzone, B. Ganem, Carbohydr. Res. 1987,
167, 305–311.
[18] V. I. Betaneli, A. Y. Ott, O. V. Brukhanova, N. K. Kochetkov,
Carbohydr. Res. 1988, 179, 37–50.
We like to thank Dr. Claudia Korb for the enzyme assays. Many thanks are
due to Dr. Ralph Kluge for the ESI-MS spectra and to Dr. Dieter Stro¨hl for
numerous NMR spectra.
[19] S. F. Nelsen, M. F. Teasley, J. Org. Chem. 1986, 51, 4319–4320.
[20] E. H. Man, F. W. Swamer, C. R. Hauser, J. Am. Chem. Soc. 1951,
73, 901–903.
[21] F. Nerdel, A. Heymons, H. Croon, Chem. Ber. 1958, 91,
938–943.
The authors have declared no conflict of interest.
[22] N. Harada, K. Nakanishi, J. Chem. Soc., Chem. Commun. 1970,
310–311.
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