Amplification of the inhibitory activity and reversal of the selectivity of miglitol by C(2′)-Monofluorination

Article abstract of DOI:10.1002/ardp.200900256

Selective monofluorination of the α-glycosidase inhibitor and antidiabetic agent miglitol at positions C(2′) or C(6) creates competitive inhibitors of glycosidases. Introducing a fluorine substituent at position C(6) results in a reduced binding to the en

Full text of DOI:10.1002/ardp.200900256

Arch. Pharm. Chem. Life Sci. 2010, 10, 583–589
583
Full Paper
Amplification of the Inhibitory Activity and Reversal of the
Selectivity of Miglitol by C(20)-Monofluorination
¨
´
Erik Prell, Claudia Korb, Ralph Kluge, Dieter Strohl, and Rene Csuk
¨
Martin-Luther-Universitat Halle-Wittenberg, Organische Chemie, Halle (Saale), Germany
Selective monofluorination of the a-glycosidase inhibitor and antidiabetic agent miglitol at positions
C(20) or C(6) creates competitive inhibitors of glycosidases. Introducing a fluorine substituent at
position C(6) results in a reduced binding to the enzyme whereas fluorination at C(20) produces an
inhibitor with an activity four times higher than the parent compound. This compound is selective for
the a-galactosidase from green coffee beans. Its screening against a panel of human cell lines showed a
low cytotoxicity, therefore, making this compound an interesting candidate for further clinical
investigations.
Keywords: Fluorination / Galactosidase / Glucosidase / Glycosidase inhibitor / Miglitol
Received: October 26, 2009; Accepted: April 7, 2010
DOI 10.1002/ardp.200900256
Introduction
Structural adjustment [9] of a known inhibitor is a good
strategy for getting stronger or more selective inhibitors. The
most pronounced effects on enzyme-substrate interactions
can be achieved by changes in the pattern and number of
hydrogen bonds between substrate and enzyme.
Replacement of a hydroxyl group by a fluorine substituent
results in the loss of a hydrogen-bond donor from the sub-
strate, whereas its ability to accept hydrogen-bonds is weak-
ened but not completely destroyed [10].
Diabetes is responsible for over one million amputations
each year. It is the largest cause of kidney failure in developed
countries. In addition, it is a major cause of blindness.
Diabetes affects about 285 million people worldwide and
this number is still increasing; the International Diabetes
Federation (IDF) [1] predicts 438 million diabetics by the year
2030.
Miglitol 1 is an oral antidiabetic drug mainly to treat
diabetes mellitus type-II. It prevents [2] the digestion of carbo-
hydrates by inhibiting a-glucosidases; therefore, 1 lowers the
degree of postprandial hyperglycemia. The iminosugar migli-
tol is used along with a proper diet to control blood sugar. In
addition, iminosugars are regarded as leads for therapeutic
reagents for several diseases, among them AIDS [3, 4], cancer
[5], Gaucher-disease, and other lysosomal storage disorders
[6]. Recently, iminosugars have been identified [7] as potent
Recently, we could show [11] that 2-fluoroderivatives of 1
are strong competitive inhibitors for various glycosidases.
This parallels previous findings for 2-chloro or 2-bromo
derivatives [12] of miglitol. Because of the excellent
screening data for the 2-fluoroderivatives, we became inter-
ested in the synthesis and biological evaluation of miglitol
derivatives carrying a fluorine substituent either at position
C(6) or C(20).
agonists of the human glucose sensor SSGLT3, and several of Results and discussion
them displayed an immunosuppressive [8] activity.
The reaction of 1 with benzaldehyde dimethylacetal in the
presence of an acid catalyst (p-TsOH or HBF4) [13, 14] failed to
give compound 2. Invariably, huge deterioration was
detected and did not allow isolating large amounts of 2 even
´
Correspondence: Prof. Dr. Rene Csuk, Bereich Organische Chemie,
Martin-Luther-Universitat Halle-Wittenberg, Kurt-Mothes-Strasse 2, D-
¨
after laborious chromatography. However, reacting
1
06120 Halle (Saale), Germany.
E-mail: rene.csuk@chemie.uni-halle.de
Fax: þ49 345 552-7030
(Scheme 1) with benzaldehyde in the presence of anhydrous
ZnCl2 [15, 16] afforded 2 in 90% yield. Reaction of 2 with trityl
chloride in pyridine/catalytic amounts of DMAP (dialkylami-
nopyridine) [17, 18] gave monotritylated 3.
Abbreviations: dialkylaminopyridine (DMAP); diethylaminosulfur
trifluoride (DAST)
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

584
E. Prell et al.
Arch. Pharm. Chem. Life Sci. 2010, 10, 583–589
Scheme 1. Synthesis of the C(20)-fluorinated analogue 7.
Scheme 2. Synthesis of the C(6)-fluorinated analogue 13.
To introduce a fluorine substituent in the C-20 position,
the hydroxyl groups were temporarily protected. Thus,
reaction of 3 with acetic anhydride/pyridine [19, 20] gave
the diacetate 4. Detritylation of 4 was performed using
p-TsOH in a MeOH/dichloromethane mixture [17, 21] and
yielded 5 (78.8%).
acetylation gave the tri-O-acetyl derivative 8 whose benzyli-
dene acetal could be cleaved regioselectively at 08C by using
NaBH3CN/F3CSO3H in THF [23]; the corresponding 6-O-benzyl
derivative 8 was formed in 89% yield.
Acetylation of 9 provided the fully protected compound 10
which was debenzylated [24] by hydrogenolysis to yield 11.
Fluorination of 11 with DAST (diethylaminosulfur trifluo-
ride) in dichloromethane gave the 6-fluoro compound 12;
Reacting alcohol 5 with DAST [22] in dry dichloromethane
gave the monofluorinated compound 6 (79.6%). Compound 6
is characterized by its 19F-NMR spectrum with a multiplet at
d ¼ –219.9 ppm; in the 13C-NMR spectrum, C-20 shows
1
no migration of acetyl groups took place and, in its H-NMR
spectrum, 12 shows JF,H6A,B ¼ 49.2–49.6 Hz. Compared to 11
in the 13C-NMR spectrum, C(6) shifts to lowered fields
(jddj ¼ 23.9 ppm). Treatment of 12 with catalytic amounts
of sodium methoxide in MeOH resulted in a smooth deacy-
lation and gave 13 in 80.2% yield.
1JC,F ¼ 169.4 Hz, whereas for C-10 at d ¼ 81.2 ppm
2JC,F ¼ 51 Hz is detected.
a
The deprotection of 6 went smoothly by treating a meth-
anolic solution of 6 with acetyl chloride for several days.
During this reaction, the acetyl groups as well as the benzy-
lidene acetal were cleaved off and 7 was obtained in 91.6%
yield. Compound 7 is characterized by its 19F-NMR spectrum:
a multiplet, present at d ¼ ꢀ219.9 ppm shows characteristic
Activities of the competitive inhibitors 7 and 13 as well as
their parent compound 1 against a panel of glycosidases in a
nitro-phenolate test [25] are reported in Table 1. Compound
13 is a weaker inhibitor as miglitol, whereas 7 shows some
interesting properties. Although 7 is a weaker inhibitor than
1 for an a-glucosidase, a b-glucosidase, and a b-galactosidase,
it is a selective and four times stronger inhibitor for the a-
galactosidase from green coffee beans.
3
2JF,H-20(‘) ¼ 47.5 Hz and JF,
¼ 27.3 and 28.7 Hz con-
0
H-1 (‘)
stants, respectively.
For the synthesis of the 6-deoxy-6-fluoro derivative 13
(Scheme 2) 2 was again used as the starting material. Its
Table 1. Nitro-phenolate test [25].
No a-glucosidase
(baker’s yeast)
b-glucosidase
(almonds)
a-galactosidase
(green coffee beans)
b-galactosidase
(E. coli)
1
7
13
9.88
16.73
n.i.
0.17
1.20
1.73
13.93
3.28
n.i.
0.19
3.64
13.73
Inhibitory activities (IC50, mM; n.i. ¼ no inhibitor) of several compounds against glycosidases. The values are the average from at least
three independent experiments; variation was ꢁ5%.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2010, 10, 583–589
Monofluorinated Miglitol Derivatives
585
In summary, introducing of a fluorine substituent at posi-
tion C-6 results in a reduced binding whereas a fluorine
substituent at position C-20 seems important for a more
selective and stronger binding to an a-galactosidase. This
finding presents 7 as an interesting new lead structure.
(R)-4,6-O-Benzylidene-N-(2-triphenylmethyloxyethyl)-1,5-
dideoxy-1,5-imino-D-glucitol 3
To a solution of 2 (10.00 g, 33.86 mmol) and DMAP (1.36 g,
11.13 mmol) in dry pyridine (100 mL), trityl chloride (28.32 g,
101.58 mmol) was added in several portions and stirring was
continued at 508C for another 48 h. The solvents were removed
under reduced pressure and the residue was dissolved in
dichloromethane (400 mL). The organic phase was washed with
water (100 mL) and the aqueous phase was extracted with
dichloromethane (6 ꢂ 200 mL). The combined organic phases
were dried (MgSO4), the solvent was removed, and the residue
subjected to chromatography (silica gel, MeOH/EtOAc, 20:80) to
afford 3 (15.09 g, 83.0%) as colorless crystals; m. p.: 92–958C;
[a]D ¼ –21.758 (c ¼ 0.55, CHCl3); Rf (MeOH/EtOAc, 10:90): 0.73;
IR (KBr) n: 3422s, 3058m, 3032m, 2871m, 1960w, 1597m, 1490m,
1449s, 1379m, 1315m, 1272m, 1220m, 1153m, 1067s, 1031s, 918m,
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), IR spectra (film or
KBr pellet) on a Perkin-Elmer FT-IR spectrometer Spectrum 1000
(Perkin-Elmer, USA), 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) instru-
ment. TLC was performed on silica gel (Merck 5554, detection by
UV absorption; Merck, Germany). The solvents were dried accord-
ing to usual procedures.
899m, 762s, 747s, 698s, 649m, 632s, 591m, 561m cmꢀ1
;
1H-NMR
(400 MHz, CDCl3) d: 7.49–7.20 (m, 20H, Ph), 5.48 (s, 1H, CH-ben-
3
2
zylidene), 4.49 (dd, 1H, J6B,5 ¼ 4.4, J6B,6A ¼ 10.5 Hz, H-6B), 3.69
3
3
3
(ddd, 1H, J2,1B ¼ 5.2, J2,3 ¼ 7.7, J2,1A ¼ 10.4 Hz, H-2), 3.65 (dd,
3
2
1H, J6A,5 ¼ 10.2, J6A,6B ¼ 10.5 Hz, H-6A), 3.50–3.40 (m, 2H, H-4,
3
H-3), 3.20–3.17 (m, 2H, H-200, H-20), 2.97 (dd, 1H, J1B,2 ¼ 5.2,
2
3
3
0
00
00
00
2
J1B,1A ¼ 11.1 Hz, H-1B), 2.76 (ddd, 1H, J1 ,2 ¼ 5.8, J1 ,
¼
2
3
5.8, J1 ,1 ¼ 11.7 Hz, H-100), 2.58 (ddd, 1H, J1 ,2 ¼ 5.8,
0
00
0
0
3
2
3
00
2
J1 ,
¼ 5.8, J1 ,1 ¼ 11.7 Hz, H-100), 2.52 (ddd, 1H, J5,6B ¼ 4.5,
0
0
00
3J5,4 ¼ 8.7, J5,6A ¼ 10.2 Hz, H-5), 2.23 (dd, 1H, J1A,2 ¼ 10.4,
2J1A,1B ¼ 11.1 Hz, H-1A) ppm; 13C-NMR (125 MHz, CDCl3) d:
144.0 (Ci-ar(trityl)), 137.5 (Car), 129.2 (Car), 128.6 (Car), 128.3
(Car), 128.0 (Car), 127.8 (Car), 127.7 (Car), 127.0 (Car), 126.3 (Car),
101.7 (CH-benzylidene), 87.0 (CPh3), 81.9 (C4), 76.3 (C3), 70.1 (C2),
69.6 (C6), 60.9 (C20), 57.5 (C5), 56.8 (C1), 51.2 (C-10) ppm; MS
(ESI – MeOH) m/z (%): 243.3 [trityl]þ (100), 538.0 [M þ H]þ (14),
560.2 [M þ Na]þ (4), 1075.0 [M2 þ H]þ (4), 1097.0 [M2 þ Na]þ (10).
Anal. calcd. for C34H35NO5 (537.65): C, 75.95; H, 6.56; N, 2.61.
Found: C, 75.82; H, 6.64; N, 2.51.
3
3
Chemistry
(R)-4,6-O-Benzylidene-N-(2-hydroxyethyl)-1,5-dideoxy-
1,5-imino-D-glucitol 2
A solution of miglitol 1 (30.00 g, 144.78 mmol) in benzaldehyde
(240 mL, 2.36 mol) was heated to 50 8C, dry ZnCl2 (50.00 g,
366.89 mmol) was added in small portions and stirring was
continued for 48 h at 508C. After cooling to 258C, water
(500 mL) was added, organic and aqueous phases were separated,
and the organic phase was extracted with water (200 mL). To the
combined organic phases a diluted solution of ammonia
(100 mL) was added and the resulting white precipitate was
filtered off. The filtrate was evaporated and the remaining res-
idue was subjected to chromatography (silica gel, MeOH/EtOAc,
2,3-Di-O-aceyl-4,6-O-benzylidene-1,5-dideoxy-N-(2-
triphenylmethyloxyethyl)-1,5-imino-D-glucitol 4
To an ice-cold solution of 3 (4.00 g, 7.44 mmol) in dry pyridine
(30 mL) acetic anhydride (2.10 mL, 22.32 mmol) was slowly
added and the resulting solution was stirred for 30 min at
08C. After stirring at room temperature for another 48 h, the
solvents were evaporated and the remaining residue was sub-
jected to chromatography (silica gel, hexane/EtOAc, 5:3) to afford
4 (3.72 g, 80.4%) as a white solid; m. p.: 80–818C; [a]D ¼ –18.468
(c ¼ 0.42, CHCl3); Rf (hexane/EtOAc, 5:3): 0.96; IR (KBr) n: 3463m,
3059m, 2958m, 2869m, 1748s, 1597w, 1491m, 1450m, 1368m,
1314m, 1244s, 1159m, 1058s, 1033s, 901m, 762m, 749m, 698m,
20:80) to afford
2 (38.49 g, 90.0%) as a colorless oil;
[a]D ¼ ꢀ43.648 (c ¼ 0.47, MeOH); Rf (MeOH/EtOAc, 20:80): 0.17;
IR (film) n: 3406s, 1608m, 1487w, 1448m, 1383m, 1218m, 1144w,
1068m, 1044m, 759m, 697m, 640m, 596m, 448m cmꢀ1 1H-NMR
;
(500 MHz, CDCl3) d: 7.51–7.49 (m, 2H, Ph), 7.36–7.32 (m, 3H, Ph),
3
5.53 (s, 1H, CH-benzylidene), 4.48 (dd, 1H, J6B,5 ¼ 4.4,
3
2
2J6B,6A ¼ 10.4 Hz, H-6B), 3.69 (dd, 1H, J6A,5 ¼ 10.4, J6A,6B
¼
10.4 Hz, H-6A), 3.66–3.64 (m, 2H, H-200, H-20), 3.58 (ddd, 1H,
3J2,1B ¼ 5.2, J2,3 ¼ 9.0, J2,1A ¼ 10.7 Hz, H-2), 3.46 (dd, 1H,
3
3
3J4,3 ¼ 9.1, J4,5 ¼ 9.0 Hz, H-4), 3.40 (dd, 1H, J3,2 ¼ 9.0,
648w, 632m, 605w cmꢀ1; H-NMR (400 MHz, CDCl3) d: 7.43–7.20
3
3
1
3J3,4 ¼ 9.0 Hz, H-3), 3.13 (dd, 1H, J1B,2 ¼ 5.2, J1B,1A ¼ 11.2 Hz,
(m, 20H, Ph), 5.45 (s, 1H, CH-benzylidene), 5.11 (dd, 1H, 3J3,2 ¼ 9.6,
3
2
H-1B), 2.78 (ddd, 1H, J1 ,2 ¼ 6.3, 3J1 ,2 ¼ 6.3, J1 ,1 ¼ 13.4 Hz,
3J3,4 ¼ 9.6 Hz, H-3), 4.97 (ddd, 1H, J2,1B ¼ 5.3, J2,3 ¼ 9.6,
3
2
3
3
0
00
00
00
00
0
H-100), 2.47 (ddd, 1H, 3J5,6B ¼ 4.4, 3J5,4 ¼ 9.1, 3J5,6A ¼ 10.4 Hz, H-5),
3J2,1A ¼ 10.0 Hz, H-2), 4.47 (dd, 1H, J6B,5 ¼ 4.3, J6B,6A
¼
3 3
3
2
2.45–2.41 (ddd, 1H, 3J1 ,2 ¼ 6.3, J1 ,
2
¼ 6.3, 2J1 ,1 ¼ 13.4 Hz, H-
10.5 Hz, H-6B), 3.66 (dd, 1H, J6A,5 ¼ 10.3, J6A,6B ¼ 10.5 Hz,
3
3
2
0
00
0
0
0
00
10), 2.27 (dd, 1H, J1A,2 ¼ 10.7, J1A,1B ¼ 11.2 Hz, H-1A) ppm; 13C-
NMR (125 MHz, CDCl3) d: 139.5 (Car), 129.9 (Car), 129.0 (Car), 127.5
(Car), 102.9 (CH-benzylidene), 83.3 (C4), 77.0 (C3), 71.2 (C2),
70.3 (C6), 59.8 (C20), 59.7 (C5), 58.8 (C1), 54.6 (C-10) ppm; MS
(ESI – MeOH) m/z (%): 296.3 [M þ H]þ (100), 318.1 [M þ Na]þ
(2), 613.0 [M2 þ Na]þ (2). Anal. calcd. for C15H21NO5 (295.32):
C, 61.00; H, 7.17; N, 4.74. Found: C, 59.83; H, 7.24; N, 4.69.
H-6A), 3.58 (dd, 1H, J4,3 ¼ 9.6, J4,5 ¼ 9.3 Hz, H-4), 3.17 (m, 2H,
3
2
H-200, H-20), 3.09 (dd, 1H, 3J1B,2 ¼ 5.3, 2J1B,1A ¼ 11.1 Hz, H-1B), 2.75
(ddd, 1H, 3J1 ,2 ¼ 5.8, J1 ,
2
¼ 5.8, 2J1 ,1 ¼ 14.2 Hz, H-100), 2.62–
3
0
00
00
00
00
0
2.55 (m, 2H, H-10, H-5), 2.33 (dd, 1H, 3J1A,2 ¼ 10.0,
2J1A,1B ¼ 11.1 Hz, H-1A), 2.03 (s, 3H, CH3, OAc), 2.00 (s, 3H, CH3,
OAc) ppm; 13C-NMR (125 MHz, CDCl3) d: 170.3 (C ¼ O, OAc), 170.1
(C ¼ O, OAc), 143.9 (Ci-ar(Trityl)), 137.5 (Car), 129.4 (Car), 128.9
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www.archpharm.com

586
E. Prell et al.
Arch. Pharm. Chem. Life Sci. 2010, 10, 583–589
(Car), 128.6 (Car), 128.2 (Car), 127.9 (Car), 127.1 (Car), 126.1 (Car),
101.2 (CH-benzylidene), 87.1 (CPh3), 79.9 (C4), 73.3 (C3), 69.9 (C2),
69.4 (C6), 60.8 (C20), 57.6 (C5), 54.6 (C1), 51.0 (C-10), 20.9 (CH3, OAc),
20.9 (CH3, OAc) ppm; MS (ESI – MeOH) m/z (%): 243.3 [trityl]þ (100),
621.9 [M þ H]þ (4), 644.3 [M þ Na]þ (38), 1242.7 [M2 þ H]þ (16),
1264.7 [M2 þ Na]þ (12). Anal. calcd. for C38H39NO7 (621.72): C,
73.41; H, 6.32; N, 2.25. Found: C, 73.30; H, 6.51; N, 2.16.
942m, 902m, 873m, 858m, 751m, 703m, 670m, 645w, 608m cmꢀ1
;
1H-NMR (500 MHz, CDCl3) d: 7.44–7.42 (m, 2H, Ph), 7.37–7.31 (m,
3
3H, Ph), 5.47 (s, 1H, CH-benzylidene), 5.20 (dd, 1H, J3,2 ¼ 9.6,
3
3
3J3,4 ¼ 9.6 Hz, H-3), 5.01 (ddd, 1H, J2,1B ¼ 5.4, J2,3 ¼ 9.6,
3J2,1A ¼ 10.2 Hz, H-2), 4.52 (m, 2H, ethylen-H-2), 4.44 (dd, 1H,
3J6B,5 ¼ 4.4, J6B,6A ¼ 10.5 Hz, H-6B), 3.69 (dd, 1H, J6A,5 ¼ 10.4,
2
3
2J6A,6B ¼ 10.5 Hz, H-6A), 3.63 (dd, 1H, 3J4,3 ¼ 9.6, 3J4,5 ¼ 9.6 Hz, H-
3
2
4), 3.22 (dd, 1H, J1B,2 ¼ 5.4, J1B,1A ¼ 11.0 Hz, H-1B), 2.88 (dddd,
3
1H, J1 ,
3
2
3
00
00
00
00
00
0
00
2
¼ 4.0, J1 ,
2
¼ 5.5, J1 ,1 ¼ 15.2, J1 ,F ¼ 29.1 Hz, H-
3 3 2
0 00
0 0 0 00
2,3-Di-O-acetyl-4,6-O-benzylidene-1,5-dideoxy-N-(2-
hydroxyethyl)-1,5-imino-D-glucitol 5
100), 2.74 (dddd, 1H, J1 ,2 ¼ 3.7, J1 ,
2
¼ 5.7, J1 ,1 ¼ 15.2,
3
3
3
J1 ,F ¼ 29.9 Hz, H-10), 2.66 (ddd, 1H, J5,6B ¼ 4.4, J5,4 ¼ 9.6,
0
To a solution of 4 (2.33 g, 3.75 mmol) in MeOH (100 mL) and
dichloromethane (50 mL), p-TsOH (1.36 g) was added and the
mixture was stirred at 258C for seven days. After neutralization
(Amberlite IRA-420, OHꢀ-form), the solvents were removed under
diminished pressure. The residue was dissolved in dichlorome-
thane (100 mL) and was washed with water (3 ꢂ 50 mL). The
organic phase was dried (MgSO4) and the solvent removed under
reduced pressure. The residue was subjected to chromatography
(silica gel, MeOH/EtOAc, 10:90) to afford 5 (1.12 g, 78.8%) as a
white solid; m. p.: 142–1448C; [a]D ¼ –41.868 (c ¼ 0.48, CHCl3); Rf
(hexane/EtOAc, 50:50): 0.16; IR (KBr) n: 3388s, 2954s, 2874s, 1742s,
1682s, 1462s, 1412s, 1375s, 1342m, 1318s, 1229s, 1135s, 1108s,
1086s, 1058s, 1028s, 999s, 984s, 962m, 924m, 906m, 881s, 845m,
800m, 768s, 721m, 704s, 685m, 637m, 605m, 593m, 573w, 563m,
542m, 527m, 508m, 466m, 440w, 419m cmꢀ1; 1H-NMR (400 MHz,
CDCl3) d: 7.42–7.39 (m, 2H, Ph), 7.35–7.32 (m, 3H, Ph), 5.46 (s,
1H, CH-benzylidene), 5.20 (dd, 1H, 3J3,2 ¼ 9.6 & 3J3,4 ¼ 9.6 Hz, H-
3J5,6A ¼ 10.4 Hz, H-5), 2.51 (dd, 1H, J1A,2 ¼ 10.2, J1A,1B
¼
3
2
11.0 Hz, H-1A), 2.05 (s, 3H, CH3, OAc), 2.04 (s, 3H, CH3, OAc)
ppm; 13C-NMR (125 MHz, CDCl3) d: 170.2 (C ¼ O, OAc), 170.2
(C ¼ O, OAc), 137.3 (Car), 128.9 (Car), 128.2 (Car), 126.0 (Car),
1
101.2 (CH-benzylidene), 81.2 (d, JC20,F ¼ 169.4 Hz, C20), 79.7
(C4), 73.9 (C3), 69.8 (C2), 69.1 (C6), 57.5 (C5), 54.5 (C1), 51.0 (d,
0
JC1 ,F ¼ 20.1 Hz, C-10), 20.9 (CH3, OAc), 20.8 (CH3, OAc) ppm; 19F-
2
3
3
00
0
NMR (188 MHz, CDCl3) d: –219.19 (dddd, JF,1 ¼ 29.1, JF,1
¼
2
2
29.9, JF,200 ¼ 47.5, JF,20 ¼ 47.5 Hz) ppm; MS (ESI – MeOH) m/z
(%): 382.2 [M þ H]þ (100), 404.2 [M þ Na]þ (26), 591.5 [M3 þ K,
H]2þ (4), 762.8 [M2 þ H]þ (61), 784.8 [M2 þ Na]þ (68). Anal. calcd.
for C19H24FNO6 (381.40): C, 59.83; H, 6.34; N, 3.67. Found: C,
59.71; H, 6.51; N, 3.55.
1,5-Dideoxy-N-(2-fluoroethyl)-1,5-imino-D-glucitol 7
To an ice-cold solution of 6 (350 mg; 0.94 mmol) in dry MeOH
(14 mL), acetyl chloride (100 mL, 1.41 mmol) was added slowly
and stirring at 08C was continued for 20 min. After stirring the
solution at 258C for four days, the solvent was removed and the
residue subjected to chromatography (silica gel, MeOH/EtOAc,
20:80) to afford 7 (180 mg, 91.6%) as colorless crystals; m. p.:
>2508C (decomposition); [a]D ¼ ꢀ4.918 (c ¼ 0.21, MeOH); Rf
(MeOH/EtOAc, 20:80): 0.14; IR (film) n: 3303s, 2920w, 2850w,
1641m, 1409s, 1337s, 1150w, 1084m, 1014s, 916w, 849w, 824w,
756w, 721w, 698m, 590m, 536m, 503m, 449m, 414w cmꢀ1; 1H-NMR
(500 MHz, CD3OD) d: 4.58 (m, 2H, H-200, H-20), 3.90 (dd, 1H,
3
3
3
3), 5.00 (ddd, 1H, J2,1B ¼ 5.3, J2,3 ¼ 9.6, J2,1A ¼ 10.4 Hz, H-2),
3
2
4.46 (dd, 1H, J6B,5 ¼ 4.4, J6B,6A ¼ 10.6 Hz, H-6B), 3.71–3.62 (m,
3
3
0
0
3H, H-6A, H-4, H-200), 3.56 (ddd, 1H, J2 ,1 ¼ 4.0, J2 ,1 ¼ 5.1,
0
3
00
2
2J20,200 ¼ 11.4 Hz, H-20), 3.26 (dd, 1H, J1B,2 ¼ 5.3, J1B,1A
¼
3
3
0
00
00
00
2
11.2 Hz, H-1B), 2.82 (ddd, 1H, J1 ,2 ¼ 5.1, J1 ,
¼ 9.5,
2
J1 ,1 ¼ 13.4 Hz, H-100), 2.61 (m, 1H, H-5), 2.39 (ddd, 1H,
00
0
3
3
2
0
00
2
J1 ,2 ¼ 4.0, J1 ,
¼ 4.0, J1 ,1 ¼ 13.4 Hz, H-10), 2.33 (dd, 1H,
0
0
0
00
3J1A,2 ¼ 10.4, J1A,1B ¼ 11.2 Hz, H-1A), 2.04 (s, 3H, CH3, OAc),
2.03 (s, 3H, CH3, OAc) ppm; 13C-NMR (125 MHz, CDCl3) d: 170.2
(C ¼ O, OAc), 170.1 (C ¼ O, OAc), 137.2 (Car), 129.0 (Car), 128.2
(Car), 126.0 (Car), 101.2 (CH-benzylidene), 79.5 (C4), 73.1 (C3), 69.5
(C2), 69.2 (C6), 58.7 (C20), 58.3 (C5), 54.0 (C1), 52.8 (C-10), 20.8 (CH3,
OAc), 20.8 (CH3, OAc) ppm; MS (ESI – MeOH) m/z (%): 380.3
[M þ H]þ (100), 402.2 [M þ Na]þ (16), 758.7 [M2 þ H]þ (11),
780.8 [M þ Na]þ (16). Anal. calcd. for C19H25NO7 (379.40): C,
60.15; H, 6.64; N, 3.69. Found: C, 59.88; H, 6.71; N, 3.64.
2
2
3
3J6B,5 ¼ 2.5, J6B,6A ¼ 12.0 Hz, H-6B), 3.81 (dd, 1H, J6A,5 ¼ 3.2,
2J6A,6B ¼ 12.0 Hz, H-6A), 3.46 (ddd, 1H, J2,1B ¼ 4.9, J2,3 ¼ 9.2,
3
3
3J2,1A ¼ 10.4 Hz, H-2), 3.32 (dd, 1H, J4,3 ¼ 9.1, J4,5 ¼ 9.0 Hz,
3
3
3
3
H-4), 3.14 (dd, 1H, J3,2 ¼ 9.2, J3,4 ¼ 9.1 Hz, H-3), 3.15 (dddd,
3
1H, J1 ,
3
2
3
00
00
00
00
00
0
00
2
¼ 5.7, J1 ,
2
¼ 6.3, J1 ,1 ¼ 15.2, J1 ,F ¼ 28.7 Hz, H-
¼ 6.0, 2J1 ,1 ¼ 15.3, 3J1 ,F ¼ 27.3 Hz, H-10),
100), 3.07 (dd, 1H, 3J1B,2 ¼ 4.9, 2J1B,1A ¼ 11.4 Hz, H-1B), 2.92 (dddd,
1H, 3J1 ,2 ¼ 3.4, J1 ,
2
3
0
00
0
0
0
00
0
2.33 (dd, 1H, 3J1A,2 ¼ 10.4, 2J1A,1B ¼ 11.4 Hz, H-1A), 2.24 (ddd, 1H,
2,3-Di-O-acetyl-4,6-O-benzylidene-1,5-dideoxy-N-(2-
fluoroethyl)-1,5-imino-D-glucitol 6
3
3
3J5,6B ¼ 2.5, J5,4 ¼ 9.0, J5,6A ¼ 3.2 Hz, H-5) ppm; 13C-NMR
1
(125 MHz, CD3OD) d: 81.3 (d, JC20,F ¼ 166.4 Hz, C20), 79.0 (C3),
To a solution of 5 (500 mg, 1.32 mmol) in anhydrous dichloro-
methane (20 mL), DAST (271 mL, 1.98 mmol) was added dropwise
under argon and the mixture was stirred at 258C for 24 h. The
solution was cooled to 08C and MeOH (1.0 mL) was added, stir-
ring continued for 30 min and the solvents were removed under
diminished pressure. The oily residue was dissolved in dichloro-
methane (130 mL) and washed with water (50 mL). The aqueous
phase was extracted with dichloromethane (3 ꢂ 100 mL). The
combined organic phases were dried (MgSO4) and the solvents
were evaporated. The remaining residue was subjected to
chromatography (silica gel, hexane/EtOAc, 50:50) to afford 6
70.5 (C4), 69.2 (C2), 66.2 (C5), 58.2 (C6), 57.2 (C1), 51.9 (d,
0
JC1 ,F ¼ 19.7 Hz, C-10) ppm; 19F-NMR (125 MHz, CD3OD) d: –
2
3
3
2
2
219.9 (dddd, JF,1 ¼ 28.7, JF,1 ¼ 27.3, JF,200 ¼ 47.5, JF,20 ¼
47.5 Hz) ppm; MS (ESI – MeOH) m/z (%): 210.3 [M þ H]þ (100).
Anal. calcd. for C8H16FNO4 (209.22): C, 45.93; H, 7.71; N, 6.69.
Found: C, 45.80; H, 7.60; N, 6.53.
00
0
2,3-Di-O-acetyl-N-(2-acetyloxyethyl)-4,6-O-benzylidene-
1,5-dideoxy-1,5-imino-D-glucitol 8
To an ice-cold solution of 2 (1.64 g, 5.55 mmol) in dry pyridine
(30 mL), acetic anhydride (2.09 mL, 22.21 mmol) was slowly
added and the mixture was stirred for 30 min at 08C. After
stirring at room temperature for another 48 h, the solvents were
evaporated and the remaining residue was subjected to
(400 mg, 79.6%) as a white solid; m. p.: 162–1648C; [a]D
¼
–48.808 (c ¼ 0.51, CHCl3); Rf (hexane/EtOAc, 50:50): 0.41; IR
(KBr) n: 3465m, 2957m, 2844m, 1746s, 1467m, 1453m, 1435m,
1371s, 1348m, 1329m, 1237s, 1167m, 1093m, 1062s, 1038s, 1016s,
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2010, 10, 583–589
Monofluorinated Miglitol Derivatives
587
chromatography (silica gel, hexane/EtOAc, 50:50) to afford 8
(1.97 g, 84.2%) as a colorless oil; [a]D ¼ –30.728 (c ¼ 0.35,
CHCl3); Rf (hexane/EtOAc, 5:3): 0.25; IR (film) n: 3469m, 2960s,
2863s, 1744s, 1499m, 1455s, 1369s, 1313s, 1229s, 1165s, 1136s,
1092s, 1035s, 904s, 875m, 754s, 701s, 641s, 606s, 546m, 450m
170.1 (C ¼ O, OAc), 137.5 (Ph), 128.5 (Car), 127.9 (Car), 127.9
(Car), 77.2 (C3), 73.5 (CH2OBn), 70.6 (C4), 69.3 (C2), 67.9 (C6),
64.1 (C5), 61.5 (C20), 53.7 (C1), 50.1 (C10), 20.9 (CH3, OAc),
20.9 (CH3, OAc), 20.8 (CH3, OAc) ppm; MS (ESI – MeOH) m/z
(%): 424.2 [M þ H]þ (100), 440.1 [M þ NH4]þ (14), 446.1
[M þ Na]þ (15), 868.5 [M2 þ Na]þ (1). Anal. calcd. for
C21H29NO8 (423.46): C, 59.56; H, 6.90; N, 3.31. Found: C, 59.41;
H, 7.02; N, 3.25.
;
cmꢀ1 1H-NMR (500 MHz, CDCl3) d: 7.43–7.40 (m, 2 H, Ph),
7.37–7.33 (m, 3 H, Ph), 5.48 (s, 1H, CH-benzylidene), 5.19 (dd,
3
3
3
1H, J3,2 ¼ 9.9, J3,4 ¼ 9.2 Hz, H-3), 5.02 (ddd, 1H, J2,1B ¼ 5.4,
3J2,3 ¼ 9.9, J2,1A ¼ 9.9 Hz, H-2), 4.46 (dd, 1H, J6B,5 ¼ 4.3,
3
3
2J6B,6A ¼ 10.5 Hz, H-6B), 4.19 (ddd, 1H, J200 ¼ 5.8, J200
¼
3
3
,10
,100
2,3,4-Tri-O-acetyl-N-(2-acetyloxyethyl)-6-O-benzyl-1,5-
dideoxy-1,5-imino-D-glucitol 10
2
3
5.8, J200,20 ¼ 11.7 Hz, H-200), 4.11 (ddd, 1H, J2 ,1 ¼ 6.5,
0
0
3
2
3
J2 ,1 ¼ 5.8, J20,200 ¼ 11.7 Hz, H-20), 3.74 (dd, 1H, J6A,5 ¼ 10.3,
0
00
2J6A,6B ¼ 10.5 Hz, H-6A), 3.66 (dd, 1H, J4,3 ¼ 9.2, J4,5 ¼ 9.2 Hz,
3
3
To an ice-cold solution of 10 (3.24 g, 7.66 mmol) in dry pyridine
(80 mL), acetic anhydride (1.44 mL, 15.32 mmol) was slowly
added and the resulting solution was stirred for 30 min at
08C. After stirring at room temperature for another 72 h, the
solvents were evaporated and the remaining residue was sub-
jected to chromatography (silica gel, hexane/EtOAc, 50:50) to
afford 13 (3.03 g, 85.0%) as a colorless oil; [a]D ¼ þ26.398
(c ¼ 0.30, CHCl3); Rf (hexane/EtOAc, 50:50): 0.54; IR (film) n:
3468w, 2947m, 2865m, 1747s, 1496m, 1455m, 1369s, 1229s,
H-4), 3.22 (dd, 1H, 3J1B,2 ¼ 5.4, 2J1B,1A ¼ 11.0 Hz, H-1B), 2.87 (ddd,
3
3
2
0
0
00
2
2
00
00
00
0
1H, J1 ,2 ¼ 5.8, J1 ,
¼ 5.8, J1 ,1 ¼ 14.3 Hz, H-100), 2.68 (ddd,
3
3
2
00
0
0
0
00
1H, J1 ,2 ¼ 6.5, J1 ,
¼ 5.8, J1 ,1 ¼ 14.3 Hz, H-10), 2.65 (ddd,
3
3
3
1H, J5,6B ¼ 4.3, J5,4 ¼ 9.2, J5,6A ¼ 10.5 Hz, H-5), 2.49 (dd, 1H,
3J1A,2 ¼ 9.9, 2J1A,1B ¼ 11.0 Hz, H-1A), 2.07 (s, 3H, CH3, OAc), 2.05 (s,
3H, CH3, OAc), 2.04 (s, 3H, CH3, OAc) ppm; 13C-NMR (100 MHz,
CDCl3) d: 170.6 (C ¼ O, OAc), 170.1 (C ¼ O, OAc), 170.1 (C ¼ O,
OAc), 137.2 (Car), 128.9 (Car), 128.2 (Car), 126.0 (Car), 101.3 (CH-
benzylidene), 79.5 (C4), 73.1 (C3), 69.6 (C2), 69.0 (C6), 61.0 (C20),
57.7 (C5), 54.4 (C1), 49.5 (C10), 20.9 (CH3, OAc), 20.9 (CH3, OAc), 20.8
(CH3, OAc) ppm; MS (ESI – MeOH) m/z (%): 422.3 [M þ H]þ (100),
444.3 [M þ Na]þ (56), 460.1 [M þ K]þ (4), 842.7 [M2 þ H]þ (14),
864.8 [M2 þ Na]þ (58), 880.7 [M2 þ K]þ (10). Anal. Calcd.
for C21H27NO8 (421.44): C, 59.85; H, 6.46; N, 3.32. Found: C,
59.72; H, 6.59; N, 3.25.
1103m, 1032s, 977m, 905m, 827w, 751m, 700m, 606m cmꢀ1
;
1H-NMR (500 MHz, CDCl3) d: 7.35–7.31 (m, 2H, Ph), 7.29–7.28
(m, 3H, Ph), 5.09–4.96 (m, 2H, H-3, H-2), 4.48 (d, 1H,
2
2
JH00 ¼ 12.0 Hz, CH002OBn), 4.43 (d, 1H, JH , H00 ¼ 12.0 Hz,
0
,H0
CH02OBn), 4.18–4.15 (m, 2H, H-200, H-20), 3.55-3.52 (m, 1H, H-6B),
3.46-3.39 (m, 2H, H-6A, H-4), 3.28–3.24 (m, 1H, H-1B), 3.14–3.08 (m,
1H, H-100), 3.04–2.95 (m, 1H, H-10), 2.82–2.74 (m, 1H, H-5), 2.54–
2.49 (m, 1H, H-1A), 2.03 (s, 3H, CH3, OAc), 2.01 (s, 3H, CH3, OAc),
1.99 (s, 3H, CH3, OAc), 1.98 (s, 3H, CH3, OAc) ppm; 13C-NMR
(125 MHz, CDCl3) d: 170.8 (C ¼ O, OAc), 170.4 (C ¼ O, OAc),
169.9 (C ¼ O, OAc), 169.6 (C ¼ O, OAc), 137.2 (Ph), 128.4 (Car),
128.1 (Car), 127.9 (Car), 74.7 (C3), 73.4 (CH2OBn), 72.0 (C4), 70.6
(C2), 66.6 (C6), 62.4 (C5), 61.4 (C20), 52.2 (C1), 49.8 (C10), 20.9 (CH3,
OAc), 20.8 (CH3, OAc), 20.7 (CH3, OAc), 20.6 (CH3, OAc) ppm; MS
(ESI – MeOH) m/z (%): 466.4 [M þ H]þ (73), 488.3 [M þ Na]þ (100),
952.5 [M2 þ Na]þ (5). Anal. calcd. for C23H31NO9 (465.49): C, 59.34;
H, 6.71; N, 3.01. Found: C, 59.17; H, 6.88; N, 2.87.
2,3-Di-O-acetyl-6-O-benzyl-1,5-dideoxy-N-(2-
acetyloxyethyl)-1,5-imino-D-glucitol 9
To an ice-cold solution of NaBH3CN (9.21 g, 146.58 mmol) in
anhydrous THF (120 mL), a solution of 8 (4.61 g, 10.94 mmol)
in anhydr. THF (50 mL) was slowly added and stirring at 08C was
continued for another hour. Trifluoromethanesulfonic acid
(6 mL) was carefully added and after stirring at 08C for another
2 h, an ice-cold solution of NaHCO3 (80 mL) was added and the
mixture was stirred at 08C for 20 min followed by stirring at 258C
for another hour. Organic and aqueous phases were separated
and the aq. phase was extracted with dichloromethane
(3 ꢂ 100 mL). The organic phases were combined, dried
(MgSO4), and the solvents were evaporated under diminished
pressure. The remaining residue was subjected to chromatog-
raphy (silica gel, hexane/EtOAc, 50:50) to afford 9 (4.14 g, 89.4%)
as a colorless oil; [a]D ¼ þ19.508 (c ¼ 0.51, CHCl3); Rf (hexane/
EtOAc, 50:50): 0.29; IR (film) n: 3465m, 2954m, 2418m, 2243w,
1739s, 1666m, 1454m, 1369s, 1237s, 1035s, 982m, 905m, 824m,
2,3,4-Tri-O-acetyl-N-(2-acetyloxyethyl)-1,5-dideoxy-1,5-
imino-D-glucitol 11
A solution of 10 (1.00 g, 2.15 mmol) in dry MeOH (30 mL) con-
taining palladium on charcoal (10%; 220 mg) was hydrogenated
(258C, 3.57 atm, 24 h). The solution was filtered through a celite
pad and this pad was washed with MeOH (2 ꢂ 100 mL). The
combined organic phases were dried (MgSO4), the solvent was
removed, and the residue subjected to chromatography (silica
gel, MeOH/EtOAc, 10:90) to afford 11 (724 mg, 89.8%) as a color-
less oil; [a]D ¼ –1.778 (c ¼ 0.40, CHCl3); Rf (MeOH/EtOAc, 10:90):
0.67; IR (film) n: 3501s, 2942s, 2861s, 1738s, 1372s, 1241s, 1110s,
743m, 700m, 606m, 523w cmꢀ1 1H-NMR (500 MHz, CDCl3) d:
;
3 3
7.36–7.27 (m, 5H, Ph), 4.94 (ddd, 1H, J2,1B ¼ 4.8, J2,3 ¼ 10.0,
3
3
3J2,1A ¼ 14.1 Hz, H-2), 4.88 (dd, 1H, J3,2 ¼ 8.4, J3,4 ¼ 14.1 Hz,
2
2
H-3), 4.55 (d, 1H, JH00 ¼ 12.0 Hz, CH002OBn), 4.51 (d, 1H, JH ,
1036s, 936w, 921w, 825w, 807w, 604w, 536w cmꢀ1
;
1H-NMR
(500 MHz, CDCl3) d: 5.10 (dd, H, J3,2 ¼ 9.6, J3,4 ¼ 9.4 Hz, H-3),
0
,H0
3
3
H00 ¼ 12.0 Hz, CH02OBn), 4.12 (m, 2H, H-200, H-20), 3.77 (dd, 1H,
3J6B,5 ¼ 4.0, J6B,6A ¼ 10.3 Hz, H-6B), 3.73 (dd, 1H, J6A,5 ¼ 3.7,
5.04 (dd, 1H, J4,3 ¼ 9.4, J4,5 ¼ 9.4 Hz, H-4), 4.94 (ddd, 1H,
2
3
3
3
2J6A,6B ¼ 10.3 Hz, H-6A), 3.64 (dd, 1H, J4,3 ¼ 8.1, J4,5 ¼ 8.4 Hz,
3J2,1B ¼ 5.1, J2,3 ¼ 9.6, J2,1A ¼ 11.0 Hz, H-2), 4.19 (ddd, 1H,
3
3
3 3
H-4), 3.16 (dd, 1H, 3J1B,2 ¼ 4.8, 2J1B,1A ¼ 11.3 Hz, H-1B), 3.01 (ddd,
3J200 ¼ 5.8, J200 ¼ 6.7, J200,20 ¼ 10.8 Hz, H-200), 4.13 (ddd,
3
2
,10
3
,100
3
1H, 3J1 ,2 ¼ 5.3, J1 ,200 ¼ 11.1, 2J1 ,1 ¼ 14.8 Hz, H-100), 2.89 (ddd,
1H, J2 ,1 ¼ 4.9, J2 ,1 ¼ 4.8, J20,200 ¼ 10.8 Hz, H-20), 3.82 (dd,
3
2
0
0
00
0
0
00
00
00
0
0
00
3
3
2
1H, J1 ,2 ¼ 6.5, J1 ,
2
¼ 6.5, J1 ,1 ¼ 14.8 Hz, H-10), 2.58 (ddd,
1H, 3J6B,5 ¼ 2.0, 2J6B,6A ¼ 13.0 Hz, H-6B), 3.43 (dd, 1H, 3J6A,5 ¼ 2.6,
0
0
0
00
3
3
3
3
2
1H, J5,6B ¼ 3.7, J5,4 ¼ 4.0, J5,6A ¼ 8.1 Hz, H-5), 2.47 (dd, 1H,
2J6A,6B ¼ 13.0 Hz, H-6A), 3.24 (dd, 1H, J1B,2 ¼ 5.1, J1B,1A
¼
3J1A,2 ¼ 10.0, J1A,1B ¼ 11.3 Hz, H-1A), 2.08 (s, 3H, CH3, OAc),
11.6 Hz, H-1B), 3.06 (ddd, 1H, J1 ,2 ¼ 4.8, J1 ,200 ¼ 6.7,
2
3
3
0
00
00
3
00
2.01 (s, 3H, CH3, OAc), 2.01 (s, 3H, CH3, OAc) ppm; 13C-NMR
(125 MHz, CDCl3) d: 171.5 (C ¼ O, OAc), 170.8 (C ¼ O, OAc),
J1 ,1 ¼ 14.8 Hz, H-100), 2.92 (ddd, 1H, J1 ,2 ¼ 4.9, J1 ,
¼ 5.8,
2
3
0
00
0
0
3
0
2
2
3
J1 ,1 ¼ 13.4 Hz, H-10), 2.55 (ddd, 1H, J5,6B ¼ 2.0, J5,4 ¼ 2.6,
0
00
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

588
E. Prell et al.
Arch. Pharm. Chem. Life Sci. 2010, 10, 583–589
2
3J5,6A ¼ 9.4 Hz, H-5), 2.49 (dd, 1H, 3J1A,2 ¼ 11.0, 2J1A,1B ¼ 11.6 Hz,
H-1A), 2.06 (s, 3H, CH3, OAc), 2.05 (s, 3H, CH3, OAc), 2.01 (s, 3H, CH3,
OAc), 2.01 (s, 3H, CH3, OAc) ppm; 13C-NMR (125 MHz, CDCl3) d:
170.8 (C ¼ O, OAc), 170.6 (C ¼ O, OAc), 170.2 (C ¼ O, OAc), 169.9
(C ¼ O, OAc), 74.2 (C3), 69.6 (C4), 69.0 (C2), 63.5 (C5), 61.5 (C20),
57.6 (C6), 53.4 (C1), 49.3 (C10), 20.9 (CH3, OAc), 20.8 (CH3, OAc), 20.7
(CH3, OAc), 20.7 (CH3, OAc) ppm; MS (ESI – MeOH) m/z (%): 376.3
[M þ H]þ (100), 398.3 [M þ Na]þ (60), 772.9 [M2 þ Na]þ (54). Anal.
calcd. for C16H25NO9 (375.37): C, 51.20; H, 6.71; N, 3.73. Found: C,
51.01; H, 6.90; N, 3.58.
2J6B,6A ¼ 10.8 J6B,F ¼ 47.8 Hz, H-6A), 3.79 (m, 2H, H-200, H-20),
3
3.80–3.55 (m, 3H, H-4, H-2, H-3), 3.13 (dd, 1H, J1B,2 ¼ 1.8,
2J1B,1A ¼ 11.6 Hz, H-1B), 2.97–2.83 (m, 3H, H-100, H-10, H-5), 2.71
(dd, 1H, J1A,2 ¼ 4.4, J1A,1B ¼ 11.6 Hz, H-1A) ppm; 13C-NMR
3
2
1
(100 MHz, CD3OD) d: 83.2 (d, J6,F ¼ 165.7 Hz, C6), 73.9–72.9
2
(m, C4, C2, C3), 68.2 (d, J5,F ¼ 19.1 Hz, C5), 61.4 (C20), 58.2
(C1), 58.2 (C10) ppm; 19F-NMR (188 MHz, CD3OD) d: ꢀ193.49
(m, 1F) ppm; MS (ESI – MeOH) m/z (%): 210.3 [M þ H]þ (100),
232.3 [M þ NH4]þ (8), 253.1 [M þ Na]þ (92), 275.1 [M þ Na,
MeOH]þ (20). Anal. calcd. for C8H16FNO4 (209.21): C, 45.93; H,
7.71; N, 6.69. Found: C, 45.71; H, 7.90; N, 6.51.
2,3,4-Tri-O-acetyl-1,5,6-trideoxy-6-fluoro-N-(2-
acetyloxyethyl)-1,5-imino-D-glucitol 12
We like to thank Mr Stefan Schwarz for the cytotoxicity assays. The cell lines
were kindly provided by Dr. Thomas Mu¨ller (Department of Haematology/
Oncology, University Halle).
To a solution of 11 (330 mg, 8.79 mmol) in anhydrous dichloro-
methane (10 mL), DAST (181 mL, 1.32 mmol) was added dropwise
and the mixture was stirred at 258C for another 4 h. The solution
was cooled to 08C, MeOH (1.0 mL) was added, and stirring at this
temperature was continued for 30 min. The solvents were
removed under diminished pressure, the oily residue was dis-
solved in dichloromethane (100 mL) and washed with water
(50 mL). The aq. phase was extracted with dichloromethane
(3 ꢂ 100 mL); the solvent was evaporated and the remaining
residue subjected to chromatography (silica gel, hexane/EtOAc,
The authors have declared no conflict of interest.
References
[1] International Diabetes Federation, IDF Diabetes Atlas, 4th Ed.,
International Diabetes Federation, Brussels 2009.
50:50) to afford 12 (175 mg, 52.8%) as
a colorless oil;
[2] W. Puls, U. Keup, H. P. Krause, G. Thomas, F. Hoffmeister,
Naturwissenschaften 1977, 64, 536–537.
[a]D ¼ þ11.558 (c ¼ 0.36, CHCl3); Rf (MeOH/EtOAc, 10:90) ¼
0.80; IR (film) n: 3474w, 2957m, 2853m, 1744s, 1637s, 1555m,
1434m, 1371s, 1227s, 1033s, 863m, 755m, 701m, 604m cmꢀ1; 1H-
NMR (500 MHz, CDCl3) d: 5.05 (dd, 1H, 3J3,2 ¼ 9.4, 3J3,4 ¼ 9.5 Hz,
[3] A. Karpas, G. W. J. Fleet, R. A. Dwek, S. Petursson, et al., Proc.
Natl. Acad. Sci. U. S. A. 1988, 85, 9229–9233.
3
3
H-3), 4.94 (dd, 1H, J4,3 ¼ 9.5, J4,5 ¼ 9.5 Hz, H-4), 4.92 (ddd, 1H,
[4] G. B. Karlsson, T. D. Butters, R. A. Dwek, F. M. Platt, J. Biol.
Chem. 1993, 268, 570–576.
3
3
3J2,1B ¼ 5.1, J2,3 ¼ 9.4, J2,1A ¼ 10.5 Hz, H-2), 4.52 (ddd, 1H,
2
2
3J6B,5 ¼ 1.8, J6B,6A ¼ 10.8 J6B,F ¼ 49.2 Hz, H-6B), 4.44 (ddd, 1H,
[5] P. E. Goss, M. A. Baker, J. P. Carver, J. W. Dennis, Clin. Cancer
Res. 1995, 1, 935–944.
2
2
3J6B,5 ¼ 4.7, J6B,6A ¼ 10.8 J6B,F ¼ 46.9 Hz, H-6A), 4.16–4.13 (m,
2H, H-200, H-20), 3.22 (dd, 1H, 3J1B,2 ¼ 5.1, 2J1B,1A ¼ 11.8 Hz, H-1B),
3
3
2
[6] T. D. Butters, R. A. Dwek, F. M. Platt, Curr. Top. Med. Chem.
2003, 3, 561–574.
3.07 (ddd, 1H, J1 ,2 ¼ 5.9, J1 ,200 ¼ 5.9, J1 ,1 ¼ 14.8 Hz, H-100),
0
00
00
00
00
0
3
3
2
0
0
0
0
00
2.94 (ddd, 1H, J1 ,2 ¼ 5.6, J1 ,
2
¼ 5.6, J1 ,1 ¼ 14.8 Hz, H-10),
3
3
3
3
[7] A. A. Voss, A. Diez-Sampedro, B. A. Hirayama, D. D. F. Loo,
E. M. Wright, Mol. Pharmacol. 2007, 71, 628–634.
2.81 (dddd, 1H, J5,6B ¼ 1.8, J5,4 ¼ 9.5, J5,6A ¼ 4.7, J5,F
¼
3
2
25.4 Hz, H-5), 2.48 (dd, 1H, J1A,2 ¼ 10.5, J1A,1B ¼ 11.8 Hz,
H-1A), 2.04 (s, 3H, CH3, OAc), 2.03 (s, 3H, CH3, OAc), 2.00 (s,
3H, CH3, OAc), 1.99 (s, 3H, CH3, OAc) ppm; 13C-NMR (125 MHz,
CDCl3) d: 170.8 (C ¼ O, OAc), 170.3 (C ¼ O, OAc), 169.9 (C ¼ O,
OAc), 169.6 (C ¼ O, OAc), 81.5 (d, 1J6,F ¼ 173.5 Hz, C6), 74.5 (C3),
[8] J. Zhou, Y. Zhang, X. Zhou, J. Zhou, et al., Bioorg. Med. Chem.
2008, 16, 1605–1612.
[9] S. M. Andersen, M. Ebner, C. W. Ekhart, G. Gradnig, et al.,
Carbohydr. Res. 1997, 301, 155–166.
2
69.0 (C2), 68.9 (C4), 62.5 (d, J5,F ¼ 18.3 Hz, C5), 61.6 (C20), 53.4
[10] T. Tsuchiya, Adv. Carbohydr. Chem. Biochem. 1990, 48, 91–
277.
(C1), 50.0 (C10), 20.9 (CH3, OAc), 20.8 (CH3, OAc), 20.7 (CH3, OAc),
20.6 (CH3, OAc) ppm; 19F-NMR (188 MHz, CDCl3) d: –215.9
3
2
2
[11] E. Prell, R. Csuk, Bioorg. Med. Chem. Lett. 2009, 19, 5673–
5674.
(ddd, 1F, JF,5 ¼ 25.4, JF,6B ¼ 46.9, JF,6A ¼ 49.2 Hz) ppm; MS
(ESI – MeOH) m/z (%): 378.1 [M þ H]þ (100), 400.1 [M þ Na]þ
(42), 776.5 [M2 þ Na]þ (1). Anal. calcd. for C16H24FNO8 (377.36):
C, 50.92; H, 6.41; N, 3.71. Found: C, 49.87; H, 6.59; N, 3.56.
[12] T. E. Barta, R. A. Mueller, US Pat. 5451679 (19.09. 1955).
[13] M. P. Dobhal, G. Li, A. Gryshuk, A. Graham, et al., J. Org.
Chem. 2004, 69, 6165–6172.
1,5,6-Trideoxy-6-fluoro-N-(2-hydroxyethyl)-1,5-imino-D-
glucitol 13
[14] M. Bodenteich, H. Griengl, Tetrahedron Lett. 1986, 27, 4291–
4292.
To a solution of 12 (360 mg, 9.54 mmol) in dry MeOH (30 mL),
sodium methoxide (10 mg, 0.19 mmol) was added, and the
solution was stirred at at 258C for 24 h. The solvent was evap-
orated and the remaining residue subjected to chromatography
(silica gel, MeOH/EtOAc, 20:80) to afford 13 (160 mg, 80.2%) as a
colorless oil; [a]D ¼ –2.158 (c ¼ 0.21, MeOH); Rf (MeOH/EtOAc,
20:80): 0.17; IR (film) n: 3396m, 2513w, 1637w, 1556w, 1400s,
[15] S. H. Khan, S. A. Abbas, K. L. Matta, Carbohydr. Res. 1989, 193,
125–139.
[16] P. Wessel, J. Carbohydr. Chem. 1988, 7, 263–269.
[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, 33–50.
1325s, 1043m, 1018w, 980w, 824w, 735w, 530w, 519w, 482w cmꢀ1
;
3
1H-NMR (500 MHz, CD3OD) d: 5.01 (ddd, 1H, J6B,5 ¼ 6.4,
[19] R. B. Cohen, K.-C. Tsou, S. H. Rutenburg, A. M. Seligman,
J. Biol. Chem. 1952, 195, 239–249.
2
3
2J6B,6A ¼ 10.8 J6B,F ¼ 44.4 Hz, H-6B), 4.63 (ddd, 1H, J6B,5 ¼ 1.8
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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[20] T. Rodrıguez-Perez, I. Lavandera, S. Fernandez, Y. S. Sanghvi,
et al., Eur. J. Org. Chem. 2007, 2769–2778.
[23] J. Hoffman, O. Theander, M. Lindberg, T. Norberg, Carbohydr.
Res. 1985, 137, 265–269.
´
´
[21] S. Penades, J. M. Coteron, J. Chem. Soc., Chem. Commun. 1992,
[24] A. E. Martell, R. M. Herbst, J. Org. Chem. 1941, 6, 878–887.
683–684.
[25] J. Conchie, A. L. Gelman, G. A. Levvy, Biochem. J. 1967, 103,
609–615.
[22] W. J. Middleton, J. Org. Chem. 1975, 40, 574–578.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com