Synthesis of all configurational isomers of 1,6-anhydro-2,3,4-trideoxy-2,3- epimino-4-fluoro-β- d -hexopyranoses

Article abstract of DOI:10.1021/jo1000912

We have prepared a full series of 1,6-anhydro-2,3,4-trideoxy-4-fluoro-2,3- epimino-β-d-hexopyranoses. The key step was the reaction of azido sulfonates possessing a free C-4 hydroxyl with DAST and subsequent LiAlH ₄ reduction. Nucleophilic displacement of the hydroxyl activated by DAST proceeded without rearrangement and with moderate to good yields. A convenient synthesis of d-mannoepimine from a readily available 3-benzylamino derivative was also developed.

Full text of DOI:10.1021/jo1000912

pubs.acs.org/joc
pensable as probes for studies of carbohydrate-protein inter-
Synthesis of All Configurational Isomers of
1,6-Anhydro-2,3,4-trideoxy-2,3-epimino-4-fluoro-
β-D-hexopyranoses
action3 and for medical imaging using positron emission
tomography, and some fluorinated nucleosides are also im-
portant therapeuticals.4 Their troublesome synthesis5 does not
cease to stimulate the efforts of synthetic chemists. In connec-
tion with our ongoing program focused on hexopyranose-
based aziridines,6 the need arose to prepare 1,6-anhydro-2,3-
epiminohexopyranoses with a strong electron-withdrawing
substituent at the pyranose carbon vicinal to the aziridine ring.
As fluorine is widely used to alter electronic properties of
carbohydrates,7 we supposed that 4-fluoro-2,3-epiminopyra-
noses may well suit this purpose and exhibit reactivity different
from their nonfluorinated counterparts. In addition, fluori-
nated epimines represent important examples of fluorinated
amino sugars with potentially interesting biochemical implica-
tions, such as precursors of enzyme inhibitors or as fluorinated
analogues of some glycoconjugate components. Here we wish
to report the synthesis of all configurational isomers of 1,6-
anhydro-2,3,4-trideoxy-4-fluoro-2,3-epimino-β-D-hexopyranoses.
We envisioned two routes to the target fluoro compounds:
(i) preparation of suitable azido sulfonates with a free C-4
hydroxyl group, subsequent displacement of the hydroxyl
with fluorine on reaction with diethylaminosulfur trifluoride
(DAST), followed by reductive aziridine ring closure, and (ii)
direct conversion of 1,6-anhydro-2,3-epiminopyranoses into
the corresponding 4-fluoro compounds on reaction with
DAST.
,†
Jindrich Karban,* Jan Sykora, Jirı
†
ꢀ
Ivana Cı
ꢁ
ꢀ
sarova, Zdenka Padelkova, and
´
Kroutil,‡
ꢀ
ꢁ ‡
ꢀ
ꢀ
ꢁ §
´
ꢀ
Milos Budesı
ꢀꢀ
ꢁ
nsky
´
†Institute of the Chemical Process Fundamentals of the
ASCR, v.v.i. Rozvojovaꢁ 135, 165 02 Praha 6, Czech Republic,
‡Faculty of Science, Charles University in Prague, Albertov 6,
§
128 43 Praha 2, Department of General and Inorganic
Chemistry, Faculty of Chemical Technology, University of
Pardubice, Studentskaꢁ 573, 532 10 Pardubice 2, Czech
Republic, and Institute of Organic Chemistry and
Biochemistry of the ASCR, v.v.i., Flemingovo naꢁm. 2, 166 10
Praha 6, Czech Republic
karban@icpf.cas.cz
Received January 20, 2010
Of these two routes, the first proved to be of general utility.
Starting 4-O-benzylated azido derivatives 1, 6, 8, 9, and 10
(Scheme 1) were prepared according to the literature proce-
dures.8 Conventional mesylation of 1 afforded 2. Azido
tosylate 14 was prepared from dianhydrotalopyranose 13
by azidolysis9 with NaN3 and subsequent tosylation. Azido
tosylate 16 was prepared using a modified literature proce-
dure.10 Synthesis of suitable azido sulfonates with a free C-4
hydroxyl group was accomplished using oxidative debenzyl-
ation of the corresponding 4-O-benzyl pyranoses with the
We have prepared a full series of 1,6-anhydro-2,3,4-
trideoxy-4-fluoro-2,3-epimino-β-D-hexopyranoses. The key
step was the reaction of azido sulfonates possessing a free
C-4 hydroxyl with DAST and subsequent LiAlH4 reduction.
Nucleophilic displacement of the hydroxyl activated by
DAST proceeded without rearrangement and with moder-
ate to good yields. A convenient synthesis of D-manno-
epimine from a readily available 3-benzylamino derivative
was also developed.
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Nat. Rev. Drug Discovery 2006, 5, 855–863.
Fluorinated carbohydrates and nucleosides have conti-
nuously received considerable attention from organic che-
mists.1 The introduction of fluorine into a carbohydrate
molecule can lead to significant changes in biochemical action,
lipophilicity, acidity, and dipole interactions in comparison
with the parent sugar.2 For example, fluorosugars are indis-
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307. (c) Dax, K.; Albert, M.; Ortner, J.; Paul, B. J. Carbohydr. Res. 2000, 327,
47–86.
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Int. Ed. 2004, 43, 5677–5679.
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Chem. Commun. 2001, 66, 799–819. (b) Cerny, M.; Elbert, T.; Pacak, J.
Collect. Czech. Chem. Commun. 1974, 39, 1752–1767.
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DOI: 10.1021/jo1000912
r
Published on Web 04/16/2010
J. Org. Chem. 2010, 75, 3443–3446 3443
2010 American Chemical Society

Karban et al.
JOCNote
SCHEME 1. Synthesis of Azido Sulfonatesa
TABLE 1. Reaction of Azido Sulfonates with DASTa
aReagents and conditions: (a) KBrO3, Na2S2O4, AcOEt, rt, 2-5 h; (b)
Tf2O, py, CH2Cl2 -15 to 0 °C, 1 h; (c) TBAN, DMF, rt, 5 h; (d) (i) NaN3,
NH4Cl, CH3OC2H4OH, H2O, reflux, (ii) TsCl, py, 80 °C.
KBrO3/Na2S2O4 system.11 Attempted inversion of config-
uration at C-4 of compound 3 by Mitsunobu reaction with
DEAD/Ph3P/4-NO2C6H4COOH to obtain compound 5
returned only the unreacted starting compound 3, probably
due to steric crowding caused by the axial OMs and CH2
groups at C-3 and C-5. On the other hand, reaction of triflate
4 with tetrabutylammonium nitrite12 proceeded smoothly
at room temperature and yielded the desired D-galacto
compound 5.
Reactions of DAST with azido sulfonates having a free
4-hydroxyl group are summarized in Table 1. It is known1c
that nucleophilic fluorination of pyranoses is complicated by
undesirable reactions, mostly rearrangements or elimina-
tions. For instance, among 31 nucleophilic fluorination reac-
tions at C-4 of hexopyranoses listed in the review article1c by
Dax et al., nine give an undesirable major product. We found
that all azido sulfonates gave only products of fluorination at
C-4. Moreover, in most cases, the stereochemistry of the
major product at C-4 corresponded to inversion of config-
uration with respect to the configuration of the hydroxyl
group in the educt. Only trans-diaxial 3-azido-2-sulfonates
11 and 12 afforded significant proportion of both epimers.
We assume that formation of noninverted products 19 and
21 is caused by competing anchimeric assistance of the
neighboring trans-diaxially disposed azido group as depicted
in Scheme 2 for reaction of 11. Because the tetrahydropyran
aConditions (based on ref 5): DAST, CH2Cl2, -20 °C to rt. b21 and
22: yield and structure determined only by NMR. Analytical samples
obtained by a semipreparative HPLC on reverse phase C18.
SCHEME 2. Suggested Mechanism for Formation of 19
1
ring is locked in C4 conformation, the attack of fluoride
anion at position 3 of the intermediate cation (Scheme 2) is
unlikely by analogy to the Furst-Plattner rule.13 The stereo-
€
chemical outcome of the reaction of 4-azido derivative 16
with DAST seems to further support this postulated mecha-
nism because only the noninverted product 25 was isolated.
A similar participation of a neighboring azido group was
also postulated14 for reaction of methyl 4,6-di-O-benzyl-
idene-3-azido-3-deoxy-R-D-altropyranoside. Fluorinated azido
mesylates 21 and 22 could not be properly separated by
column chromatography on silica gel, and we obtained only
enriched fractions. Fluoro derivative 22 crystallized from
the respective enriched chromatographic fraction and was
obtained in 80% purity. The corresponding tosylates 19 and
(11) Adinolfi, M.; Barone, G.; Guariniello, L.; Iadonisi, A. Tetrahedron
Lett. 1999, 40, 8439–8441.
(12) Dong, H.; Pei, Z.; Ramstrom, O. J. Org. Chem. 2006, 71, 3306–3309.
(13) (a) F€urst, A; Plattner, P. A. 12th International Congress on Pure and
Applied Chemistry, New York, 1951, Book of Abstracts, p 409. (b) Karban, J.;
Kroutil, J. Adv. Carbohydr. Chem. Biochem. 2006, 60, 28-104 and discussion
therein.
(14) Vera-Ayoso, Y.; Borrachero, P.; Cabrera-Escribano, F.; Carmona,
ꢁ
A. T.; Gomez-Guillen, M. Tetrahedron: Asymmetry 2004, 15, 429–444.
ꢁ
3444 J. Org. Chem. Vol. 75, No. 10, 2010

Karban et al.
JOCNote
SCHEME 3. Skeletal Rearrangements of 26 and 29
SCHEME 4. Reductive Cyclizationa
aReagents and conditions: LiAlH4, THF, -15 °C to rt, 24 h.
20 of the same configuration could be separated by careful
column chromatography.
Scheme 3. It is noteworthy that the major product 27 of
reaction with DAST has the same configuration at C-9 (C-5
in numbering of 26) as the product of methanolysis 30. The
stereochemical outcome of this reaction was attributed to
a concerted process with synchronous formation of C-4
carbocation, a shift from C-6 to C-4, and an equatorial
attack of the nucleophile at C-5.16 The 1,2-alkyl shift in-
volved in formation of products 27 and 28 seems to indicate
that with some substrates the fluorination with DAST
should follow a SN1 cationic mechanism rather than the
otherwise more usual SN2 mechanism.17 The SN2-type dis-
placement reactions at C-4 of mannose derivative 26 are
probably suppressed because of the steric hindrance exerted
by the substituents at the β-face of the substrate.18
The structures of the 4-hydroxy and 4-fluoro derivatives
were determined from 1H and 13C NMR spectra. The
gCOSY and gHSQC spectra were measured for structural
1
assignment of H and 13C signals (see Supporting Infor-
mation). The position of the hydroxyl group was determined
from the observation of the J-coupling of 6-10 Hz to H-4.
The trans-diaxial disposition of substituents at C-2 and C-3
was manifested by small values of J-couplings of the equa-
torial H-2 and H-3 protons (J(2,1) = 1.1-1.7, J(2,3) =
1.3-2.8, J(3,4ax) = 4.7-6.1, and J(3,4eq) = 1.3-1.7 Hz);
the position of the tosyl/mesyl group is manifested by the
1
significant downfield H NMR chemical shift compared to
the chemical shift of the azide group. The increase of
coupling constants J(2,3) and J(3,4) of 19 and 21 indicates
a certain population of the boat form BO,3.
15 The equatorial
Treatment of azido sulfonates 17, 18, 19, and 23 with
lithium aluminum hydride afforded the respective aziridine
derivatives 31-33 (Scheme 4). The D-taloepimine 34 was
prepared by treatment of a mixture of mesylate 20 and tosylate
22. The epimines 31-34 represent all possible configurations
within 1,6-anhydro-β-D-hexopyranose series. Epimines 31-34
are stable crystalline compounds which sublimate around
position of H-2 and H-3 is further supported by the observa-
tion of long-range couplings J(1,3), J(2,4), J(3,5) ∼ 0-1.7.
Coupling constants J(5,6en) = 0.6-1.2 Hz and J(5,6ex) =
4.9-5.9 Hz are in agreement with O1E conformation of the
five-membered dioxolane ring.
Introduction of the fluorine atom causes additional split-
ting of the 1H and 13C NMR signals in the pyranose moiety.
This splitting is also reflected in the 19F NMR spectra of
17-24 in which the characteristic doublet of triplet or plain
doublet can be usually found for axial and equatorial F-4,
respectively. In most cases, both epimers were prepared, and
thus we can generalize that the axial fluorine atom in position
4 shows not only geminal coupling to H-4 but also strong
vicinal coupling to H-3 and H-5 while the equatorial F-4
possesses, in addition to the geminal coupling, only weak
vicinal couplings.
During preliminary experiments, we tried to introduce
fluorine at C-4 by the reaction of 2,3-di-O-benzylidene-
D-mannosane 26 with DAST. Here a skeletal rearrangement
took place to provide branched-chain pyranosyl fluorides 27
and 28 (Scheme 3). Both products are crystalline com-
pounds, but 28 contained impurities and decomposed on
standing at 4 °C within several weeks whereas anomer 27 is
stable. The structures of products 27 and 28 were determined
by X-ray analysis. A similar rearrangement also took place16
on methanolysis of diazo compound 29 and yielded methyl
pyranoside 30. The formation of these rearrangement pro-
ducts is consistent with initial formation of C-4 carbo-
cationic species followed by 1,2-alkyl shift, as depicted in
1
90 °C. They show the characteristic H NMR chemical shift
of H-2 and H-3 under 3 ppm, which is accompanied by the rise
of the J(2,3) up to 4.9-5.8 Hz, indicating the EO conformation
of the tetrahydropyran ring. The NMR assignment and
structures were confirmed by X-ray crystallography of all
epimines 31-34 (see Supporting Information).
Finally, we turned our attention to direct conversion of
4-hydroxy-2,3-epimines into 4-fluoro analogues. During
preliminary experiments, we discovered that treatment of
galactoepimine 35 with DAST in dichloromethane at -50 °C
resulted in formation of 4-fluoro-2,3-mannoepimine 37 as a
major product instead of the expected 2-fluoro-3,4-talo-
epimine (Scheme 5). Epimine 37 was probably formed by
nucleophilic aziridine ring opening of the intermediate 36
with fluoride anion and subsequent aziridine ring closure at
C-2. 2-Fluoro-galactoepimine 39 was detected by NMR as a
minor product but could not be isolated by column chromato-
graphy as a pure compound. A very convenient prepara-
tion of epimine 37 consists of treatment of readily available19
3-benzylamino derivative 38 with DAST. Mannoepimine 37
was isolated in one step in 49% yield. Possible formation of 37
from 38 involves activation of the 4-OH group by DAST
(17) Baptista, L.; Bauerfeldt, G. F.; Arbilla, G.; Silva, E. C. J. Mol. Struct.
(THEOCHEM) 2006, 761, 73–81.
(18) Capon, B. Chem. Rev. 1969, 69, 407–498.
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(19) Kroutil, J.; Trnka, T.; Budesınsky, M.; Cerny, M. Collect. Czech.
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(15) Trnka, T.; Cerny, M.; Budesınsky, M.; Pacak, J. Collect. Czech.
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Chem. Commun. 1975, 40, 3038.
(16) Alexander, M. S.; Horton, D. Carbohydr. Res. 2007, 342, 31–43.
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Chem. Commun. 1998, 63, 813–825.
J. Org. Chem. Vol. 75, No. 10, 2010 3445

Karban et al.
JOCNote
SCHEME 5. Reaction of 35, 38, and 40-43 with DAST
Experimental Section
Example procedures are given below. Full experimental
details are available in Supporting Information.
1,6-Anhydro-2-azido-2,4-dideoxy-4-fluoro-3-O-methanesulfo-
nyl-β-D-galactopyranose (17). A solution of hydroxy mesylate 3
(444 mg, 1.67 mmol) in dichloromethane (3 mL) was added to a
stirred, cooled (-15 °C) solution of DAST (0.7 mL, 5.30 mmol)
in dichloromethane. The cooling bath was removed after 20 min,
and the reaction mixture was allowed to stand at rt for 48 h. TLC
in ethyl acetate indicated one product (Rf 0.6). The reaction
mixture was diluted with dichloromethane, MeOH (2 mL) was
added dropwise under cooling to quench the reaction, and the
reaction mixture was successively washed with 5% HCl and
aqueous NaHCO3, dried, and concentrated. Chromatography
in 1:1 ethyl acetate-hexane afforded 17 (316 mg, 71%): mp
81-83 °C (ethanol), [R]25D þ55 (c 0.21, CHCl3). Anal. Calcd for
C7H10FN3O5S: C, 31.46; H, 3.77; N, 15.72. Found: C, 31.53; H,
3.82; N, 15.39.
1,6-Anhydro-2,3,4-trideoxy-4-fluoro-2,3-epimino-β-D-gulo-
pyranose (31). A suspension of LiAlH4 (75 mg, 1.98 mmol) in
THF (2.5 mL) was added dropwise to a stirred, cooled (-15 °C)
solution of fluoro derivative 17 (208 mg, 0.78 mmol) in THF
(5 mL). The cooling bath was removed after 30 min, and stirring
continued overnight. TLC in acetone and 10:1 dichloromethane-
methanol revealed one product (Rf 0.41). The remaining LiAlH4
was decomposed by addition of wet diethyl ether. The white
precipitate was filtered off and washed with THF, and
the combined filtrates were concentrated. Chromatography in
20:1 dichlorormethane-methanol afforded epimine 31 (76 mg,
followed by aziridine ring closure at C-4 to give galactoepimine
35. Aziridine ring closure at C-2 directly from 38 is unlikely
because C-4 hydroxyl consistently exhibits higher reactivity
than C-2 hydroxyl.19 Hydrogenolytic de-N-benzylation of 37
gave free epimine 33.
Encouraged by these results, we subjected 2,3-epimino
derivatives 40 and 42 to treatment with DAST in dichloro-
methane at -50 °C. However, these experiments only resulted
in formation of complex syrupy mixtures which contained no
fluoro compounds according to 19F NMR. N-Protection by
the benzyl group brought no improvement because N-benzyl-
epimines 41 and 43 gave again only complex mixtures
with no fluorine-containing products according to 19F
NMR. Epimines 40-43 were prepared by published8b,19
procedures.
In conclusion, we have developed a methodology for the
introduction of fluorine at C-4 of 1,6-anhydro-β-D-hexopyra-
noses substituted at C-2 and C-3 by trans-diaxially disposed
azide and alkene/arenesulfonyloxy groups. Subsequent reduc-
tive cyclization provided the corresponding 4-fluoro-2,3-
epimino derivatives in all possible configurations. The reacti-
vity of these fluoro epimines is currently being studied, and the
results will be reported in due course.
67%): mp 95-97 °C (ethanol-ether), [R]25 þ48 (c 0.17,
D
CHCl3). Anal. Calcd for C6H8FNO2: C, 49.65; H, 5.56; N,
9.65. Found: C, 49.67; H, 5.47; N, 9.51.
Acknowledgment. We thank the Grant Agency of AS CZ
for grant support (Grant No. IAA400720703). The purchase/
service of the X-ray diffractometers in Prague and Pardubice
was supported by the Ministry of Education (Grant Nos.
MSM0021620857 and VZ0021627501). NMR measure-
ments were supported by the Grant Agency of ASCR, Grant
No. IAA400720706.
Supporting Information Available: Full experimental de-
tails, tables of NMR chemical shifts and coupling constants,
crystallographic data, ORTEP projections, and copies of 1H
and 13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
3446 J. Org. Chem. Vol. 75, No. 10, 2010