A Convenient Route to Peracetylated 3-Deoxy-3-fluoro Analogues of d -Glucosamine and d -Galactosamine from a ?erny Epoxide

Article abstract of DOI:10.1055/s-0033-1341187

Peracetylated 3-deoxy-3-fluoro analogues of d-glucosamine and d-galactosamine 3 and 4, respectively, were prepared from 1,6:2,3-dianhydro-4-O- benzyl-β-d-mannopyranose (6). Azidolysis of 6 followed by reaction with diethylaminosulfur trifluoride gave 1,6-

Full text of DOI:10.1055/s-0033-1341187

LETTER
▌1253
lAetteCr onvenient Route to Peracetylated 3-Deoxy-3-fluoro Analogues of D-Glu-
cosamine and D-Galactosamine from a Černý Epoxide
Fluorinated Analogues of D-Glucosamine and D-Galactosamine
Jindřich Karban,* Štěpán Horník, Lucie Červenková Šťastná, Jan Sýkora
Institute of Chemical Process Fundamentals of the ASCR, v. v. i., Rozvojová 135, 16502 Prague 6, Czech Republic
Fax +420(2)20920661; E-mail: karban@icpf.cas.cz
Received: 24.02.2014; Accepted after revision: 19.03.2014
whereas the syntheses of 3 proved to be challenging ow-
Abstract: Peracetylated 3-deoxy-3-fluoro analogues of D-glucos-
ing to a low yield (28% and 10%, respectively) of the crit-
amine and D-galactosamine 3 and 4, respectively, were prepared
1
d,3
ical fluorination step. Interestingly, much better yields
from 1,6:2,3-dianhydro-4-O-benzyl-β-D-mannopyranose (6). Azi-
dolysis of 6 followed by reaction with diethylaminosulfur trifluo- in the fluorination step were reported for naphthyl-
ride gave 1,6-anhydro-2-azido-4-O-benzyl-2,3-dideoxy-3-fluoro- methyl (93%) and ethylthio (50%) 2-phthalimido-2,3-
β-D-glucopyranose (9). Cleavage of the internal acetal, hydrogena- dideoxy-3-fluoro-4,6-di-O-acetyl-β-D-glucopyranosides.
1
b
4
tion and acetylation yielded 3. De-O-benzylation of 9 followed by a
Ideally, a synthetic route to fluorinated hexosamines
configurational inversion at C4 gave 1,6-anhydro-2-azido-2,3-dide-
should also be capable of providing them as selectively
oxy-3-fluoro-β-D-galactopyranose (18), which provided 4 after
protected derivatives with free C4 or C6 hydroxy groups
cleavage of the 1,6-anhydro bridge, reduction, and acetylation.
that can be utilized in glycosylation reactions and other
Key words: carbohydrates, fluorine, antitumor agents, nucleophil-
synthetic transformations.
ic fluorination, amino sugars
OAc
OAc
O
O
Fluorinated derivatives of D-glucosamine and D-galactos-
amine have recently attracted more attention for their abil-
ity to inhibit cancer-cell growth.1 For instance,
peracetylated 4-deoxy-4-fluoro-D-glucosamine 1 and its
F
AcO
AcO
F
OR
AcHN OAc
AcHN
1
R = Ac
2 R = H
3
OH
HO
1
-deacetylated analogue 2 inhibited proliferation of the
F
OAc
AcO
O
human prostate cancer cell line PC-3, the latter showing a
1
a
O
higher inhibitory effect than cisplatin and 5-fluorouracil.
In addition, treatment of cancer cells with 1 and 2 (Figure
) reduced the expression of highly branched N-glycans
F
AcHN
OH
AcHN OAc
1
5
4
1
a
which are essential for cancer progression. Peracetylated
-deoxy-3-fluoro-D-glucosamine 3 inhibited proliferation
and biosynthesis of hyaluronic acid in the pancreatic can-
Figure 1 Examples of fluorinated hexosamines
3
cer cell line KP1-NL, probably by termination of a hyal- In the context of our interest in fluorinated 1,6-anhydro-β-
uronan chain.1d Furthermore, fluorinated hexosamines D-hexopyranoses we set out to investigate their usefulness
have potential as components of modified tumor-associat- as intermediates in the preparation of fluorinated hexos-
ed carbohydrate antigens vaccines in which they can en- amines. Here we report the synthesis of compounds 3 and
hance hydrolytic stability without compromising 4 starting from 4-O-benzylated 1,6:2,3-dianhydro-β-D-
2
immunogenicity. Thus, synthetic analogues of Thomsen– mannopyranose 6 (one of the Černý epoxides) readily
5
6
Friedenreich antigen containing 6-deoxy-6-fluoro-N-ace- available from D-glucal or from levoglucosan. We based
tyl-D-galactosamine 5 along with 6-deoxy-6-fluoro-D-ga- our approach on the transformation of the known key in-
lactose were prepared and incorporated into antitumor termediate 9 (Scheme 1) which is formed by regioselec-
vaccines which elicited a strong immune response in tive azidolysis of the oxirane ring of 6 followed by
mice.2
To advance our knowledge of the biological activity and
therapeutic potential of these and other fluorinated hexos-
amines it is critical that reliable synthetic routes to these
compounds are available. This is particularly true for 3-
fluoro analogues 3 and 4 (Figure 1) because, to our knowl-
edge, a synthesis of 4 (or any D-galacto configured 3-flu-
orohexosamine derivative) has not yet been reported
OAc
O
AcO
F
OAc
OAc
AcHN
O
O
O
O
F
3
refs. 7, 8
O
AcO OAc
OBn
OBn N3
O
F
6
9
AcHN
SYNLETT 2014, 25, 1253–1256
Advanced online publication: 10.04.2014
4
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1341187; Art ID: ST-2014-B0160-L
Georg Thieme Verlag Stuttgart · New York
Scheme 1 Retrosynthetic plan
©

1254
J. Karban et al.
LETTER
stereoselective introduction of fluorine at C3 on reaction Because deoxofluorination of D-gluco derivative 8 by
7
with diethylaminosulfur trifluoride (DAST) as outlined treatment with DAST was clean and high-yielding, we
in Scheme 1.
first attempted the synthesis of 4 by deoxofluorination of
5 which is a D-galacto isomer of 8. To this end 1,6:2,3-
dianhydromannopyranose 7 available from 6 by hydro-
1
This allowed the amino group to be installed and conve-
niently masked as a non-participating azide function dur-
ing the synthesis. Simultaneous protection of the
anomeric and primary hydroxyls in the form of an internal
acetal, on the other hand, facilitated protecting group ma-
nipulations.
1
3
genolysis was converted into 1,6:2,3-dianhydrotalopy-
1
4
ranose 13 which was O-benzylated to 14. Azidolysis
1
5
gave known 15 (Scheme 4). However, treatment of 15
with DAST (in boiling benzene or in dichloromethane at
r.t.), failed to produce the desired 3-fluoro derivative 16
Oxirane ring-opening of dianhydromannopyranose 6 with
lithium azide in DMF–water proceeded trans-diaxially
furnishing the known 2-azido derivative 8 (Scheme 2).
Substitution of the C3 hydroxyl by fluorine on reaction
with DAST was accomplished using a minor modification
of the reported procedure. We hypothesize that retention
of configuration during the substitution step can result
from the participation of the neighboring benzyloxy group
rather than the azido group (vide infra).10
(
Scheme 4). The starting 15 was recovered whereas pro-
longed reaction resulted in a very slow formation of a
mixture of several unknown fluorinated products as indi-
8
19
cated by F NMR. Because compounds 8 and 15 differ
only in the orientation of the C4 benzyloxy group, the
striking difference in their reactivity towards DAST can
9
indicate that fluorination of 8 involves participation of the
10a,b
vicinal antiperiplanar benzyloxy group at C4.
This can
10b
occur by formation of a transient oxiranium ion. Such
assistance is impossible in 15 because the benzyloxy
group is synclinal. The participation of the vicinal antiperi-
O
O
O
O
O
OH
O
F
a
b
10c,d
O
planar azido group, although postulated in other cases,
seems to be inoperative here.
OR
OBn N3
OBn N3
6
7
R = Bn
R = H
8
9
O
O
O
O
O
O
a
c
b
7
HO
BnO
Scheme 2 Reagents and conditions: (a) LiN , DMF, H O, 110 °C,
0%; (b) DAST, benzene, 75 °C, 88%, see also ref. 7.
3
2
7
13
1
4
O
O
OH
O
F
d
A palladium-catalyzed hydrogenolytic removal of the O-
benzyl protecting group with a parallel reduction of the
azide, and subsequent acetylation afforded acetamide 10.
Sulfuric acid catalyzed acetolysis of the 1,6-anhydro
BnO
O
BnO
N3
N3
1
5
1
6
bridge on reaction with acetic anhydride gave a mixture Scheme 4 Reagents and conditions: (a) see ref. 14; (b) BnBr, NaH,
from which 1,2-oxazoline 11 crystallized as the main THF, r.t., 79%; (c) LiN , NH Cl, MeOC OH, reflux, 81%; (d)
DAST, benzene, reflux; or DAST, CH Cl , r.t.
H
2 4
3
4
component instead of the expected 3. To circumvent the
2
2
problem of oxazoline formation, the cleavage of the 1,6-
anhydro bridge was done first by treatment with acetic an- This difficulty was overcome by placing the inversion of
1
1
hydride/triethylsilyl triflate (TESOTf). Resulting diace- configuration after fluorination in the reaction sequence
tate 12 was then hydrogenolyzed (Pd/C and H ) and (Scheme 5). Thus, 3-fluoro derivative 9 was de-O-ben-
2
1
6
acetylated to give the required peracetylated 3-deoxy-3- zylated by treatment with NaBrO /Na S O system and
3
2
2
4
fluoro-D-glucosamine 3 (Scheme 3).12
the resulting hydroxy derivative 17 was converted into C4
epimer 18 using trifluoromethanesulfonylation followed
1
7,18
OAc
by reaction with tetrabutylammonium nitrite.
Acetol-
O
F
b
O
a
O
AcO
F
9
N
O
O
OAc NHAc
O
F
F
a
b
HO
O
O
c
10
11
9
OAc
OAc
OH
N3
N3
1
8
d
17
O
O
BnO
AcO
F
F
OAc
AcO
OAc
AcO
OAc
AcHN
OAc
N3
d
O
c
O
3
F
12
F
OAc
AcHN
N3 OAc
Scheme 3 Reagents and conditions: (a) 10% Pd/C, H , EtOH, HCl,
r.t., then Ac O, py, 37%; (b) Ac O, AcOH, H SO , r.t., 40%; (c)
2
1
9
4
2
2
2
4
Ac O, TESTf, r.t., 96%; (d) Pd/C, H , EtOH, HCl, then Ac O, py,
2
2
2
Scheme 5 Reagents and conditions: (a) NaBrO , Na S O , EtOAc–
3
2
2
4
72%.
H O, 81%; (b) Tf O, CH Cl , py, 0 °C, then Bu NO , DMF, r.t., 67%;
2
2
2
2
4
2
(
c) Ac O, TESOTf, r.t., 86%; (d) Pd/C, H , EtOH, Ac O, r.t., 65%.
2
2
2
Synlett 2014, 25, 1253–1256
© Georg Thieme Verlag Stuttgart · New York

LETTER
Fluorinated Analogues of D-Glucosamine and D-Galactosamine
1255
ysis of the internal acetal (Ac O, triethylsilyl triflate), pal-
(8) For the preparation of 8 using other sources of the azide
2
nucleophile, see e.g.: (a) Paulsen, H.; Stenzel, W. Chem.
Ber. 1978, 111, 2348. (b) Karban, J.; Buděšínský, M.;
Černý, M.; Trnka, T. Collect. Czech. Chem. Commun. 2001,
66, 799. (c) Hesek, D.; Lee, M.; Zhang, W.; Noll, B. C.;
Mobashery, S. J. Am. Chem. Soc. 2009, 131, 5187.
ladium-catalyzed reduction with H , and acetylation
2
yielded 4.19
The structures of the target products 3 and 4 were con-
1
13
19
firmed by multinuclear 1D ( H, C and F) and 2D
gCOSY and gHSQC) NMR spectroscopy. The position
(d) Paulsen, H.; Bünsch, A. Angew. Chem. Int. Ed. 1980, 19,
(
902. (e) Arndt, S.; Hsieh-Wilson, L. C. Org. Lett. 2003, 5,
of the fluorine atom in the structure is reflected by the
large value of the respective geminal coupling constant
4
179.
(
9) We found that three equivalents of DAST and the oil bath
temperature of 75 °C were enough to carry the reaction to
completion. The original procedure in ref. 7 used nine
equivalents of DAST in refluxing benzene.
2
JHF = 50 Hz, and by the characteristic downfield shift of
the geminal proton (H–C–F) which resonates at δ = 4.60–
n
4
.97. The value of JCF reflects the distance of the respec-
tive carbon atom from fluorine in the molecule. The D-
(10) (a) Dax, K.; Albert, M.; Hammond, D.; Illaszewicz, C.;
Purkarthofer, T.; Tscherner, M.; Weber, H. Monatsh. Chem.
2002, 133, 427. (b) Takahashi, Y.; Vasella, A. Helv. Chim.
Acta 1992, 75, 1563. (c) Karban, J.; Sýkora, J.; Kroutil, J.;
Císařová, I.; Padělková, Z.; Buděšínský, M. J. Org. Chem.
2010, 75, 3443. (d) Biggadike, K.; Borthwick, A. D.; Evans,
D.; Exall, A. M.; Kirk, B. E.; Roberts, S. M.; Stephenson, L.;
Youds, P. J. Chem. Soc., Perkin Trans. 1 1988, 549.
(11) Zottola, M.; Rao, B. V.; Fraser-Reid, B. J. Chem. Soc.,
Chem. Commun. 1991, 969.
gluco configuration of 3 is manifested by the large values
3
3
3
of the vicinal coupling constants J , J , and J = 8.6–
2
,3
3,4
4,5
1
0.5 Hz whereas D-galacto configuration of 4 displays
3
3
lower values of J3 and J = 1.4–3.7 Hz. The α-anomer
,4
4,5
and β-anomer can be distinguished by the different values
3
of the J1 constant (ca. 8.7 Hz for β, ca. 3.7 Hz for α). The
,2
position of the NHAc group in the structure is confirmed
2
by geminal coupling J2 = 8 Hz.
,NH
(
12) Compound 3 was formed as an anomeric mixture (α/β =
In conclusion, 1,6:2,3-dianhydro-4-O-benzyl-β-D-man-
nopyranose 6 has been conveniently transformed into per-
acetylated 3-deoxy-3-fluoroanalogues of D-glucosamine
and D-galactosamine in four and six steps, respectively, in
an overall yield of 43% and 19%, respectively. In addi-
tion, our approach furnished selectively protected fluoro-
hydrins 17 and 18 which are useful synthetic
intermediates with potential for a regioselective function-
alization or glycosylation at C4. Investigation towards this
application and an extension of our methodology to other
fluorinated hexosamines is currently underway in our lab-
oratory.
19
8
3:12; estimated by F NMR of the crude product). The
anomers were separated and purified chromatographically in
an i-PrOH–CHCl –petroleum ether (2:5:5) solvent mixture
3
yielding 322 mg (64%) of the α-anomer and 40 mg (12%) of
the β-anomer. Analytical data for the α-anomer: mp 132–134
1
°
C (EtOAc–heptane); [α] +81 (0.12, CHCl ). H NMR (300
D
3
MHz, CDCl ): δ = 2.02 (s, 3 H, NHCOCH ), 2.08 (s, 3 H,
3
3
COCH ), 2.10 (s, 3 H, COCH ), 2.16 (s, 3 H, COCH ), 3.97
3
3
3
2
3
(
m, 1 H, H-5), 4.11 (ddd, J
J6en,F = 2.0 Hz, 1 H, H-6en), 4.29 (dd, J
= 12.5 Hz, J
= 2.0 Hz,
= 12.5 Hz,
6
en,6ex
6en,5
5
2
6en,6ex
3
2
J
6ex,5 = 4.2 Hz, 1 H, H-6ex), 4.62 (ddd, overlap with H-3,
3
J3,F = 55.8 Hz, J = 10.2 Hz, 1 H, H-2), 4.65 (ddd, overlap
3,2
3
3
with H-2, J = 10.2 Hz, J = 8.6 Hz, 1 H, H-3), 5.33 (ddd,
3
,2
4,3
3
3
3
J4,F = 12.5 Hz, J = 10.3 Hz, J = 8.6 Hz, 1 H, H-4), 5.52
d, J
.6 Hz, 1 H, H-1). C NMR (75 MHz, CDCl ): δ = 20.30 (s,
4,5
4,3
2
3
4
(
3
= 8.1 Hz, 1 H, NH), 6.20 (dd, J = 3.6 Hz, J
=
2
,NH
2,1
1,F
1
3
Supporting Information for this article is available online at
3
COCH ), 20.33 (s, COCH ), 20.50 (s, COCH ), 22.80 (s,
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
n
ungIifoop
r
t
3
3
3
2
NHCOCH ), 50.73 (d, J = 18.0 Hz, C-2), 61.24 (s, C-6),
8.04 (d, J = 18.4 Hz, C-4), 69.46 (d, J = 6.8 Hz, C-5),
89.64 (d, JC,F = 189.9 Hz, C-3), 91.05 (d, JC,F = 9.2 Hz,
C-1), 168.92 (s, COCH ), 169.57 (s, COCH ), 170.62 (s,
3
C,F
2
3
6
C,F
C,F
3
1
References and Notes
3
3
(
1) (a) Nishimura, S.-I.; Hato, M.; Hyugaji, S.; Feng, F.;
Amano, M. Angew. Chem. Int. Ed. 2012, 51, 3386. (b) Xue,
J.; Kumar, V.; Khaja, S. D.; Chandrasekaran, E. V.; Locke,
R. D.; Matta, K. L. Tetrahedron 2009, 65, 8325. (c) Goon,
S.; Bertozzi, C. R. J. Carbohydr. Chem. 2002, 21, 943.
19
COCH ), 171.24 (s, COCH ). F NMR (282 MHz, CDCl3):
3
3
δ = –199.77 (m). Anal. Calcd for C H FNO : C, 48.1; H,
1
4
20
8
5.8; N, 4.0. Found: C, 48.0; H, 5.7; N, 3.9. Analytical data
for the β-anomer: mp 172–174 °C (EtOAc–heptane); [α] +5
D
1
(
c 0.18, CHCl ). H NMR (300 MHz, CDCl ): δ = 2.00 (s, 3
3 3
(d) Wasonga, G.; Tatara, Y.; Kakizaki, I.; Huang, X.
H, NHCOCH ), 2.08 (s, 3 H, COCH ), 2.10 (s, 3 H, COCH ),
3
3
3
J. Carbohydr. Chem. 2013, 32, 392.
2
.12 (s, 3 H, COCH ), 3.77 (m, 1 H, H-5), 3.88 (m, 1 H, H-
3
(
2) (a) Hoffmann-Röder, A.; Kaiser, A.; Wagner, S.; Gaidzik,
N.; Kowalczyk, D.; Westerlind, U.; Gerlitzki, B.; Schmitt,
E.; Kunz, H. Angew. Chem. Int. Ed. 2010, 49, 8498.
2
3
5
2), 4.11 (ddd, J
= 12.5 Hz, J
= 2.0 Hz, J
= 1.5
6
ex,6en
6en,5
6en,F
2
3
Hz, 1 H, H-6en), 4.27 (dd, J
1
=
Hz, J = 8.8 Hz, 1 H, H-4), 5.68 (d, J
NH), 5.99 (d, J = 8.6 Hz, 1 H, H-1). C NMR (75 MHz,
= 12.5 Hz, J
= 4.5 Hz,
6
en,6ex
3
6ex,5
2
3
3
H, H-6ex), 4.90 (ddd, J = 50.9 Hz, J = 10.0 Hz, J
3
,F
3,2
4,3
(b) Oberbillig, T.; Mersch, C.; Wagner, S.; Hoffmann-
3
8.8 Hz, 1 H, H-3), 5.18 (ddd, J = 12.5 Hz, J = 10.0
4
,F
4,5
Röder, A. Chem. Commun. 2012, 48, 1487. (c) Oberbillig,
T.; Lowe, H.; Hoffmann-Roder, A. J. Flow Chem. 2012, 2,
3
2
= 8.3 Hz, 1 H,
4,3
2,NH
13
3
2
,1
8
3.
CDCl ): δ = 20.34 (s, COCH ), 20.38 (s, COCH ), 20.52 (s,
3
3
3
(3) Sharma, M.; Bernacki, R. J.; Hillman, M. J.; Korytnyk, W.
Carbohydr. Res. 1993, 240, 85.
2
COCH ), 23.05 (s, NHCOCH ), 54.73 (d, J = 18.5 Hz, C-
), 61.40 (s, C-6), 68.26 (d, J = 18.8 Hz, C-4), 71.74 (d,
3
3
C,F
2
2
J
(
C,F
1
(4) Kajihara, Y.; Kodama, H.; Endo, T.; Hashimoto, H.
Carbohydr. Res. 1998, 306, 361.
3
= 8.0 Hz, C-5), 90.23 (d, J = 188.9 Hz, C-3), 91.07
C,F
C,F
3
d, J = 10.1 Hz, C-1), 169.70 (s, COCH ), 169.85 (s,
C,F
3
(
(
5) Xue, J.; Guo, Z. Tetrahedron Lett. 2001, 42, 6487.
6) Trnka, T.; Černý, M. Collect. Czech. Chem. Commun. 1971,
19
COCH ), 171.07 (s, COCH ), 171.22 (s, COCH ). F NMR
282 MHz, CDCl ): δ = –194.24 (dt, J
12.5 Hz, J
3
3
3
2
3
(
=
= 50.9 Hz, J
3
H3,F H4,F
3
6, 2216; and references therein.
3
= 12.4 Hz). Anal. Calcd for C H FNO : C,
H2,F 14 20 8
(7) Faghih, R.; Escribano, F. C.; Castillon, S.; Garcia, J.;
48.1; H, 5.8; N, 4.0. Found: C, 47.7; H, 5.8; N, 3.8.
Olesker, A.; Thang, T. T. J. Org. Chem. 1986, 51, 4558.
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1253–1256

1256
J. Karban et al.
LETTER
3
(
(
13) Rehnberg, N.; Magnusson, G. J. Org. Chem. 1990, 55, 5467.
14) Karban, J.; Císařová, I.; Strašák, T.; Červenková Šťastná, L.;
Sýkora, J. Org. Biomol. Chem. 2012, 10, 394.
(dddd, 2J4,OH = 8.8 Hz, 3J4,F = 26.4 Hz, 3J4,5 = 4.5 Hz, J
=
4,3
2
3
4.5 Hz, 1 H, H-4), 4.20 (dd, J
= 7.9 Hz, J
= 1.5 Hz, J
= 1.5 Hz,
6
ex,6en
6en,5
3
3
3
1 H, H-6en), 4.51 (dddd, J
= 4.5 Hz, J
6
en,5
6ex,5 4,5
4
4
(
(
15) Oberdorfer, F.; Haeckel, R.; Lauer, G. Synthesis 1998, 201.
16) Adinolfi, M.; Barone, G.; Guariniello, L.; Iadonisi, A.
Tetrahedron Lett. 1999, 40, 8439.
= 4.5 Hz, J = 1.5 Hz, 1 H, H-5), 4.80 (ddddd, J = 1.5
Hz, J = 1.5 Hz, J = 4.5 Hz, J = 48.2 Hz, J = 1.5
Hz, 1 H, H-3), 5.48 (dd, J = 1.5 Hz, J = 1.5 Hz, 1 H, H-
1). C NMR (75 MHz, CDCl ): δ = 60.83 (d, J = 25.1 Hz,
C-2), 63.77 (d, J = 3.4 Hz, C-6), 64.99 (d, J = 17.7 Hz,
C,F C,F
C-4), 74.18 (s, C-5), 88.91 (d, J = 183.0 Hz, C-3), 99.51
(s, C-1). F NMR (282 MHz, CDCl ): δ = –199.79 (ddddd,
3
,
5
3
,
1
3
3
3
4
2,3
4,3
3,F
3,5
3
4
2
,1
3,1
1
3
2
(
17) (a) Lattrell, R.; Lohaus, G. Liebigs Ann. Chem. 1974, 1974,
3 C,F
4
2
901. (b) Albert, R.; Dax, K.; Link, R. W.; Stütz, A. E.
1
Carbohydr. Res. 1983, 118, C5. (c) Emmadi, M.; Kulkarni,
S. S. J. Org. Chem. 2011, 76, 4703.
C,F
1
9
3
2
3
3
5
(
18) Preparation of Compounds 17 and 18 from 9: A solution
of NaBrO (725 mg, 4.80 mmol) in H O (16 mL) was added
JH3,F = 48.2 Hz, J
1.2 Hz, J
= 26.4 Hz, J
= 14.7 Hz, J
=
H4,F
H2,F
6ex,F
3
= 4.0 Hz). HRMS (APCI): m/z [M + H – N2]
3
2
F,OH
to a solution of 9 (439 mg, 1.57 mmol) in EtOAc (22.5 mL).
calcd for C H FNO : 162.0561; found: 162.0564.
6 9 3
A solution of Na S O (836, 4.79 mmol) in H O (32 mL) was
(19) Compound 4 was obtained after chromatography in EtOAc
2
2
4
2
1
9
added dropwise in 10 min under stirring. TLC (EtOAc–
petroleum ether, 1:2) indicated absence of 9 after 2 h of
vigorous stirring at r.t. The organic phase was separated and
washed with aq Na S O . The aqueous phase was extracted
in 86% yield as an anomeric mixture (α/β = 72:28, F NMR)
which contained about 7% of unknown fluorine-containing
1
9
by-products ( F NMR). Recrystallization from CH Cl –
2
2
Et O yielded 46% of the pure α-anomer. Crystallization of
2
2
3
2
with EtOAc (3 ×). The combined organic extracts were
washed with brine, dried (Na SO ) and concentrated.
the mother liquor provided additional 19% of a mixture of
both anomers (β/α = 89:11, estimated by F NMR) without
contaminating by-products.
1
9
2
4
Chromatography in heptane–EtOAc–25% aq NH –H O
3
2
(
40:40:9:2) yielded 17 (240 mg, 81%); mp 102–105 °C
Analytical data for α-anomer: mp 177–178 °C (EtOAc); [α]D
1
1
(MeOH); [α] –6.0 (c 0.18, CHCl ). H NMR (300 MHz,
+133 (c 0.09, CHCl ). H NMR (300 MHz, CDCl ): δ = 2.01
D
3
3
3
2
CDCl ): δ = 2.60 (d, J
= 10.7 Hz, 1 H, OH), 3.62 (ddddd,
(s, 3 H, NHCOCH ), 2.04 (s, 3 H, COCH ), 2.15 (s, 3 H,
3
4,OH
3
3
3
3
3
4
J2,1 = 1.9 Hz, J = 1.7 Hz, J = 13.9 Hz, J = 1.7 Hz, 1
COCH ), 2.17 (s, 3 H, COCH ), 4.10 (m, 3 H, H-5, H-6en,
3 3
2,3
2,F
2,4
2
3
3
3
3
H, H-2), 3.77 (ddddd, J
= 10.7 Hz, J = 13.9 Hz, J
H-6ex), 4.74 (overlap 2 × ddd, J = 11.1 Hz, J = 3.4 Hz,
4
4
,OH
4,F
4,5
3,2
4,3
3
2
=
1.8 Hz, J = 1.7 Hz, J = 1.7 Hz, 1 H, H-4), 3.84 (ddd,
2 H, H-3, H-2), 5.47 (d, J
= 8.7 Hz, 1 H, NH), 5.62 (m,
1 H, H-4), 6.25 (dd, J = 3.9 Hz, J = 3.7 Hz, 1 H, H-1).
4
,3
2,4
2,NH
2
3
5
2
4
J6en,6ex = 7.7 Hz, J
= 5.8 Hz, J
= 2.5 Hz, 1 H, H-
6ex,5
6ex,F
2,1
1,3
2
3
13
6
4
ex), 4.11 (dd, J
.59 (dddd, J6 = 1.3 Hz, J
= 7.7 Hz, J
= 1.3 Hz, 1 H, H-6en),
C NMR (75 MHz, CDCl ): δ = 20.30 (s, COCH ), 20.32 (s,
6
ex,6en
6en,5
3
3
3
3
3
= 5.8 Hz, J = 1.8 Hz, 1
COCH ), 20.54 (s, COCH ), 22.91 (s, NHCOCH ), 47.45 (d,
en,5
6ex,5
4,5
3
3
3
4
3
3
2
2
1
4
H, H-5), 4.62 (ddddd, J = 1.9 Hz, J = 1.7 Hz, J = 1.7
Hz, J = 44.2 Hz, 1 H, H-3), 5.50 (dd, J = 1.9 Hz, J
=
JC,F = 19.2 Hz, C-2), 61.21 (d, J = 2.1 Hz, C-6), 66.43 (d,
JC,F = 16.9 Hz, C-4), 68.37 (d, J = 5.5 Hz, C-5), 86.37 (d,
JC,F = 192.1 Hz, C-3), 91.64 (d, J = 9.3 Hz, C-1), 169.07
3
,1
2,3
4,3
C,F
3
3
4
3
3
,F
2,1
3,1
C,F
1
3
3
1.9 Hz, 1 H, H-1). C NMR (75 MHz, CDCl ): δ = 58.75
3
C,F
2
4
(d, J = 25.4 Hz, C-2), 64.87 (d, J = 4.7 Hz, C-6), 67.74
(s, COCH ), 170.50 (s, COCH ), 170.71 (s, COCH ), 170.94
C,F
C,F
3 3 3
2
1
19
(d, J = 26.6 Hz, C-4), 75.69 (s, C-5), 89.93 (d, J
=
(s, COCH ). F NMR (282 MHz, CDCl ): δ = –202.53 (ddd,
3 3
C,F
C,F
1
9
2
3
3
1
85.5 Hz, C-3), 99.78 (s, C-1). F NMR (282 MHz, CDCl ):
JH3,F = 46.7 Hz, J
= 12.4 Hz, J
= 5.2 Hz). HRMS
3
H2,F
H4,F
2
3
3
δ = –180.50 (dddd, J
=
3
= 44.2 Hz, J
= 2.5 Hz). Anal. Calcd for C H FN O : C,
= 13.9 Hz, J
(ESI): m/z [M + Na] calcd for C H FNO Na: 372.1071;
H3,F
H4,F
H2,F
14 20 8
5
13.9 Hz, J
found: 372.1065.
Analytical data for β-anomer: H NMR (300 MHz, CDCl ):
6
ex,F
6
8
3
3
1
8.1; H, 4.3; N, 22.2. Found: C, 38.3; H, 4.2; N, 21.8.
3
Product 17 was dissolved in CH Cl (2.7 mL) containing
δ = 1.99 (s, 3 H, NHCOCH ), 2.04 (s, 3 H, COCH ), 2.12 (s,
2
2
3
3
3
pyridine (0.7 mL). Trifluoromethanesulfonic acid anhydride
0.45 mL, 2.73 mmol) was added under cooling (–40 °C) and
3 H, COCH ), 2.15 (s, 3 H, COCH ), 3.99 (ddd, J = 1.4
3 3 4,5
3
3
(
Hz, J
= 6.5 Hz, J
= 3.2 Hz, 1 H, H-5), 4.16 (m, 3 H,
6en,5
6
ex,5
2
3
stirring. The temperature was allowed to reach 0 °C, the
reaction mixture was poured onto ice and extracted into
CH Cl (4 ×). The combined extracts were dried (Na SO )
H-6ex, H-6en, H-2), 4.97 (ddd, J = 46.8 Hz, J = 10.6
Hz, J = 3.7 Hz, 1 H, H-3), 5.57 (ddd, J = 1.4 Hz, J
3,F 3,2
3
3
3
4
,3
4,5
2
4,3
3
= 3.7 Hz, J = 5.5 Hz, 1 H, H-4), 5.70 (d, J
= 8.3 Hz,
2
2
2
4
4,F
2,NH
13
2
and concentrated to afford crude triflate (390 mg, 96%),
1 H, NH), 5.91 (d, J = 8.7 Hz, 1 H, H-1). C NMR (75
2,1
which was immediately dissolved in anhyd DMF (4.0 mL).
Tetrabutylammonium nitrite (0.9 g, 3.12 mmol) was added
and stirring at r.t. was continued for 12 h. The reaction
mixture was concentrated in vacuo to about 1/3 its volume
and chromatographed (EtOAc–petroleum ether 1:2) to
MHz, CDCl ): δ = 20.30 (s, COCH ), 20.32 (s, COCH ),
3
3
3
2
20.53 (s, COCH ), 23.10 (s, NHCOCH ), 51.76 (d, J
=
3
3
C,F
2
4
19.6 Hz, C-2), 61.23 (d, J = 2.8 Hz, C-6), 66.25 (d, J
C,F
C,F
3
1
= 16.6 Hz, C-4), 70.88 (d, J = 6.2 Hz, C-5), 87.41 (d, J
C,F
3
C,F
= 193.1 Hz, C-3), 91.57 (d, J = 10.5 Hz, C-1), 169.77 (s,
C,F
afford 18 (161 mg, 67%); mp 44–46 °C; [α] +47 (c 0.14,
COCH ), 170.41 (s, COCH ), 170.95 (s, COCH ), 171.22 (s,
D
3
3
3
1
2
19
CHCl ). H NMR (300 MHz, CDCl ): δ = 2.41 (dd, J
=
COCH ). F NMR (282 MHz, CDCl ): δ = –198.59 (ddd,
3
3
4,OH
3
3
3
3
2
3
3
8
.8 Hz, J
= 4.0 Hz, 1 H, OH), 3.70 (ddd, J = 1.5 Hz,
JH3,F = 46.8 Hz, J
= 10.3 Hz, J
= 5.5 Hz). HRMS
F,OH
2,1
H2,F
H4,F
3
3
2
J2,3 = 1.5 Hz, J = 14.7 Hz, 1 H, H-2), 3.73 (ddd, J
(ESI): m/z [M + Na] calcd for C H FNO Na: 372.1071;
2,F
6en,6ex
14 20 8
3
5
=
7.9 Hz, J
= 4.5 Hz, J = 1.2 Hz, 1 H, H-6ex), 4.06
found: 372.1066.
6
ex,5
6ex,F
Synlett 2014, 25, 1253–1256
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.