Skeletal rearrangements resulting from reactions of 1,6:2,3- and 1,6:3,4-dianhydro-β-d-hexopyranoses with diethylaminosulphur trifluoride

Article abstract of DOI:10.1039/c1ob06336g

A complete series of eight 1,6:2,3- and 1,6:3,4-dianhydro-β-d- hexopyranoses were subjected to fluorination with DAST. The 1,6:3,4- dianhydropyranoses yielded solely products of skeletal rearrangement resulting from migration of the tetrahydropyran oxygen

Full text of DOI:10.1039/c1ob06336g

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PAPER
Skeletal rearrangements resulting from reactions of 1,6:2,3- and
1,6:3,4-dianhydro-b-D-hexopyranoses with diethylaminosulphur trifluoride†
a
b
a
a
a
ˇ
ˇ
ˇ
Jindrˇich Karban,* Ivana C´ısarˇova´, Toma´sˇ Strasˇa´k, Lucie Cervenkova´ Stastna´ and Jan Sy´kora
Received 5th August 2011, Accepted 27th September 2011
DOI: 10.1039/c1ob06336g
A complete series of eight 1,6:2,3- and 1,6:3,4-dianhydro-b-D-hexopyranoses were subjected to
fluorination with DAST. The 1,6:3,4-dianhydropyranoses yielded solely products of skeletal
rearrangement resulting from migration of the tetrahydropyran oxygen (educts of D-altro and D-talo
configuration) or of the 1,6-anhydro bridge oxygen (D-allo, D-galacto). The major products yielded by
the 1,6:2,3-dianhydropyranoses were compounds arising from nucleophilic substitution, with
configuration at C4 either retained (D-talo, D-gulo) or inverted (D-manno), or from C6 migration
(D-allo). The minor products in the 1,6:2,3-series resulted from migration of the tetrahydropyran
oxygen (D-gulo) or the oxirane oxygen (D-manno), or from nucleophilic substitution with retention of
configuration (D-manno). The structure of most of the rearranged products was verified by X-ray
crystallography.
group participation.1c,8 On the other hand, DAST-induced one-
pot rearrangement and fluorination can also be intentionally
employed to prepare a variety of fluorinated products.3g
Introduction
Fluorinated sugars represent an important class of modified car-
bohydrates and considerable efforts have been expended on their
synthesis.1 The most attention has been devoted to deoxyfluoro
carbohydrates, which arise formally from the replacement of a
hydroxyl with a fluorine atom. The reasons for their synthesis are
the similarity between the fluorine atom and the hydroxyl group
in size, the ability of fluorine to participate in hydrogen bonding,2
and significant changes in conformational, stereoelectronic and
lipophilic properties induced by introduction of fluorine into
a molecule.3 For example, incorporation of fluorine into the
carbohydrate moiety of nucleosides has a profound impact on
their biological activity, which fact has been successfully employed
in development of drugs.4 Nucleophilic substitution is frequently
utilized for regio- and stereoselective introduction of fluorine. This
is usually achieved by treatment of sulphonates with a suitable
source of fluoride anion,5 by direct reaction of an unprotected
hydroxyl group with diethylaminosulphur trifluoride (DAST),6 or
by nucleophilic cleavage of an epoxide.7 Although the reaction
with DAST has found widespread application, it often suffers
from side reactions such as skeletal rearrangements (typically
ring contractions in the case of pyranosides) and neighbouring
We have recently reported the synthesis of
a full se-
ries of 4-fluoro-2,3-epimino derivatives of 1,6-anhydro-b-D-
hexopyranoses.9 The key synthetic step was a reaction between
DAST and an azido tosylate possessing a free hydroxyl at C4
as illustrated in Scheme 1 for the synthesis of 1,6-anhydro-2,3,4-
trideoxy-2,3-epimino-4-fluoro-b-D-gulopyranose (2) from tosylate
1.9 While the reaction with DAST proceeded smoothly with good
stereoselectivity and moderate yields, and without rearrange-
ments, the overall synthetic sequence required additional steps
including introduction of a benzyloxy group and debenzylation.
We hypothesised that such protecting group manipulation might
be avoided if fluorine were introduced into the pyranose moiety
by treatment of 1,6:2,3- or 1,6:3,4-dianhydro-b-D-hexopyranoses
(also called epoxides) with DAST, as outlined in Scheme 1
for the synthesis of 2 from dianhydropyranose 3. Because
aInstitute of the Chemical Process Fundamentals of the ASCR, v.v.i. Rozvo-
jova´ 135, 165 02, Praha 6, Czech Republic. E-mail: karban@icpf.cas.cz;
Fax: +420-220- 920-661; Tel: + 420-220-390-252
bFaculty of Science, Charles University in Prague, Albertov 6, 128 43, Praha 2
† Electronic supplementary information (ESI) available: Experimental
details for compounds 8, 11, 12, 31, 36 and 37, computational details,
crystallographic data, copies of NMR spectra. CCDC reference numbers
832048–832066. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1ob06336g
Scheme 1 Synthesis of epimine 2 from 1 (ref. 9) and suggested synthesis of
2 from dianhydroderivative 3. Reagent and conditions: (a) DAST, CH2Cl2,
-20 ◦C–rt, 71%; (b) LiAlH4, THF, -15 ◦C–rt, 67%.
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Table 1 Reactions of dianhydrohexopyranoses with DAST
dianhydrohexopyranoses possess just one free hydroxyl, the
need for protection and deprotection steps is eliminated. Fur-
thermore, the annulation of a three-membered ring to the
1,6-anhydrohexopyranose skeleton will probably induce higher
rigidity of the tetrahydropyran ring along with deviation of its
conformation from the chair conformation towards the envelope
conformation.10 We wished to find out whether these confor-
mational changes could suppress rearrangements by moving the
bonds that usually participate in a skeletal rearrangement out
of the antiperiplanar arrangement. To this end we investigated
the reactions of all possible configurational isomers of 1,6:2,3-
and 1,6:3,4-dianhydro-b-D-hexopyranoses with DAST having the
following results.
Starting
Entry material
Product, isolated yield
1
9
2
3
4
11
6
Results and discussion
Preparation of the starting dianhydropyranoses is summarized
in Scheme 2. We found it convenient to prepare most of the
dianhydropyranoses from tosylate 1.11 First, published procedures
were employed to synthesize 3,12 4,13 6,13 and 9,12 and then the
dianhydrohexoses 8, 11, and 12 were obtained from their epimers
3, 9, and 4 by conversion into triflates 7, 10, and 5 followed by
treatment with tetrabutylammonium nitrite in DMF.14 Epoxide
14 was prepared from the readily available 2,3-isopropylidene-D-
mannosan 13.15
14
5
6
8
4
7
8
3
12
Reaction conditions: DAST, CH2Cl2, -50 ◦C–rt, 30–48 h. apairs 17 and
18, and 22 and 25, are inseparable by column chromatography, the yields
estimated by NMR from the combined yield after column chromatography
purification.
Scheme 2 Synthesis of dianhydrohexopyranoses.
With all the required dianhydropyranoses in hand, we subjected
them to reaction with DAST. We used the reaction conditions
that we had applied before for the reaction of epimino pyranoses
with DAST.9 The results are given in Table 1. The 1,6:3,4-
dianhydropyranoses 9, 11, 6, and 14 yielded exclusively the
rearranged fluorinated products (see entries 1–4). Owing to
rearrangement the products were glycosyl fluorides and were
isolated mostly as anomeric pairs (entries 1–3). We were able to
separate the anomeric pairs 15/16 and 19/20 by silicagel column
chromatography. For 17/18 this was not possible, but a crystal
suitable for X-ray structure determination of the major product
17 was obtained by crystallization. Product 21 was prepared as a
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Scheme 3 Reaction of 28, 31 and 37 with DAST.
pure crystalline compound but it decomposed within a few weeks
of storage in a refrigerator.
were prepared by reaction of dianhydroderivatives 30 and 34 with
lithium azide in DMF.18
The prevalent reaction mode for 1,6:2,3-dianhydropyranoses 8,
4, and 3 was fluorination at C4 with retention (entries 5 and 6) or
inversion (entry 7) of configuration with no rearrangement. How-
ever, fluorination of D-allo-epoxide 12 yielded only a rearranged
product (27, entry 8).
Among rearranged tricyclic products, which we obtained via
fluorination of dianhydropyranoses, compounds 15, 16, 17, 18,
and 24 possess tricyclic ring systems already known in carbohy-
drate chemistry, though with a different substitution pattern: trian-
hydroallitol 40,20 methyl 2,6:3,4-dianhydro-a-D-altropyranoside
41,21 and 5-O-benzoyl-l,6:2,3-dianhydro-a-L-talofuranose 4222
(Fig. 1).
Fluorination of 4 and 3 also provided rearranged compounds
24 (26%) and 26 (9%) respectively. The two epimeric substitution
products 22 and 25 obtained on fluorination of the D-manno-
epoxide 3 could not be separated either by column chromatog-
raphy or by crystallization, and compound 25 could thus be
characterized only by its 1H, 13C and 19F NMR spectra. Despite the
low isolated yield of 21 and 27 (entries 4 and 8), GC-MS analysis
of the reaction after work-up did not indicate any other products,
whereas TLC analysis of the reaction mixture showed an immobile
component at the start. This may indicate extensive decomposition
or polymerization. Generally, low yield of fluorinated products is
encountered relatively often in reactions with DAST.1c,8,16
Because fluorination of 4 and 8 resulted in unexpected reten-
tion of configuration, structurally related 1,6-anhydro-2,3-di-O-
benzylidene-b-D-talopyranose 28 was prepared17 for comparison
and subjected to DAST fluorination, which also furnished non-
inverted 4-fluoro product 29 as the major product (Scheme 3).
NMR performed after chromatographical purification showed
another fluorine-containing product in about 5% yield, most
probably a C4-epimer of 29, which could not be separated by
column chromatography. Pure 29 was obtained by crystallization
in 32% yield.
Fig. 1
Mechanistic considerations
It is generally accepted that reaction of an alcohol with DAST con-
verts the hydroxyl group into a good leaving group by formation
of an unstable R-OSF2NEt2 intermediate.8 This intermediate can
undergo nucleophilic substitution with a fluoride anion, or with
another external or intramolecular nucleophile, or it can react by
elimination. The structure of the products which we obtained gives
evidence of seven different reaction pathways with respect to the
mechanism and the migrating atoms and bonds (see Scheme 5).
Because reactions of 1,6:3,4-dianhydro-b-D-hexopyranoses with
DAST failed to provide the desired 2-deoxy-2-fluorohexopyranose
derivatives due to skeletal rearrangements, we attempted to intro-
duce fluorine at C2 by DAST fluorination of known azido alcohol
31.18 This reaction, however, also resulted in rearrangement
producing fluorides 32 and 33. In another attempt at fluorination
at C2 we employed azido tosylate 3618 (Scheme 3), which was
oxidatively debenzylated19 to 37 using the KBrO3/Na2S2O4 system
and subjected to reaction with DAST to yield 2-fluoropyranose
38, contaminated to the extent of about 20% by another product
inseparable by column chromatography. An analytical sample
of 38 was prepared by a semipreparative reverse phase HPLC,
whereas the unknown minor product was obtained only as an
enriched HPLC fraction. The minor product was tentatively
assigned the structure of the glycosyl fluoride 39 on the basis
Scheme 4 Reaction of 43 with DAST.
1) SN2 substitution with inversion of configuration. With our
substrates this mechanism operates only in formation of 4-fluoro
epoxide 22 from 3 and 2-fluoropyranose 38 from 37.
2) Migration of the tetrahydropyran oxygen O5 from C1 to C2
with contraction of the tetrahydropyran ring and fluorine entry
at C1. This mechanism was observed in fluorination of 9 and
14 (see Table 1 entries 1, 4). Both reagents have an equatorial
C2 hydroxyl which is antiperiplanar to the migrating O5–C1
1
of H, 13C and 19F NMR spectra. Azido derivatives 31 and 35
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unprotected 1,6-anhydro-b-D-gluco- and galactopyranose were
reported to give very low yields (of 10% and 6.5% respectively)
of 2,6-anhydrohexopyranosyl fluorides.16
5) Migration of the oxirane oxygen from C3 to C4 with
enlargement of the oxirane ring into oxetane and fluorine entry at
C3. This pathway applies for the formation of the minor product
26. Although produced in low yield, this compound is a rare
example of a fluorinated oxetane (the few examples of isolated
fluorooxetanes hitherto reported belong to d-amino acids26 and
nucleosides27) and is unique in its incorporation of a fluorooxetane
into a tricyclic ring system. Migration of the oxirane ring probably
involves formation of a transient oxonium species and products 25
and 26 are most likely formed via the same species with fluorine
entry at C4 or C3, respectively, (Scheme 5).
6) 1,2-Alkyl shift of C6 from C5 to C4 with enlargement of
the dioxolane ring and fluorine entry at C5. This pathway applies
to formation of 27 from 12. We have also observed9 this type of
rearrangement upon reaction of 2,3-di-O-benzylidenemannosane
46 with DAST to afford 47 and 48 (Scheme 6). Since 1,2-alkyl shifts
are typically displayed by carbocations, we assume that formation
of 27, 47, and 48 may indicate a more carbocationic character
of the intermediate species. This assumption is supported by a
recently reported skeletal rearrangement of diazo compound 49
to 50 during methanolysis (Scheme 6) because diazo compounds
are expected to decompose through generation of carbocations.28
Scheme 5 Schematic representation of the mechanistic pathways and the
postulated oxonium intermediate species discussed in the text.
bond. These results confirm the strong migratory aptitude of the
tetrahydropyran oxygen upon reaction of C2–OH with DAST as
documented by Dax for other pyranoses.8 Only substrates of b-
D-manno configuration were reported to undergo fluorination at
C2 by the SN2 mechanism with configurational inversion as the
preferred reaction mode.8,23 The formation of 38 from the b-D-
manno derivative 37 was in accordance with this finding.
3) Migration of the tetrahydropyran oxygen O5 from C5 to
C4 with contraction of the tetrahydropyran ring and fluorine
entry at C5. This pathway applies only for the formation of
the minor product 24 from 4. Parallel formation of 23 suggests
that migration of the ring oxygen probably proceeds via an
intermediate epi-oxonium ion comprising O5–C4–C5 (Scheme 5
and discussion under (7)). A published precedent from outside the
1,6-anhydrohexopyranose series is the formation of the furanoid
by-products 45 during DAST fluorination of hexopyranosides 43
(Scheme 4).24
4) Migration of the oxygen O6 of the 1,6-anhydro bridge
from C1 to C2 with an enlargement of the dioxolane ring and
fluorine entry at C1. This reaction pathway applies to reaction
of 6, 11 and 31. Migration of the 1,6-anhydro bridge oxygen
from C1 to C2 is a reaction pattern sometimes observed25 with
1,6-anhydrohexopyranoses possessing an axial leaving group at
C2, and parallel results were obtained for DAST fluorination of
1,6-anhydro-3,4-di-O-isopropylidene-b-D-galactopyranose.8 Even
Scheme 6 Rearrangements of 46 and 49.
7) Unexpectedly, dianhydro derivatives 8 and 4 reacted with
DAST to give the products 22 and 23 of nucleophilic substitution
with retention of configuration. To retain configuration at C4 the
fluoride anion must approach the molecule from the sterically
more hindered b-face. The 1,6-anhydro-2,3-di-O-benzylidene-
talopyranose 28 prepared for comparison was also found to
provide mainly the non-inverted 4-fluoro product 29 of the D-
talo configuration (Scheme 3). In contrast, we have found that
D-galacto-azido sulphonates 51a, b reacted with DAST chiefly to
yield the 4-fluoro products 52a, b with inversion of configuration
at C4 (Scheme 7).30
To account for retention of configuration in fluorination of 8,
4, and 28 we assume the involvement of the pyranose oxygen O5
in the nucleophilic displacement, which proceeds by a transient
epi-oxonium ion without actual ring rearrangement. Product
24 is most probably formed through the same epi-oxonium
intermediate as product 23 with fluorine entry at C5 (Scheme
5). Although ring oxygen participation is commonly observed
in reactions of hexopyranoses with DAST, it normally results
in ring contraction.8 Nevertheless, a bicyclic epi-oxonium ion
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the bonds which participate in skeletal rearrangements (i.e. the
migrating and leaving bond) are in the range of 161–172◦. Thus
the deviation from the ideal antiperiplanar arrangement is clearly
negligible and cannot suppress the rearrangement. To present
unequivocal evidence for the structure of the fluorinated products,
we produced crystals suitable for X-ray crystallography for all
compounds prepared by fluorination of dianhydrohexopyranoses
except for 18 and 25, which could not be isolated as pure
compounds, and 24, which did not crystallize. The structural
analysis revealed four groups of products differing from each
other in the molecule geometry of the carbohydrate skeleton
(Fig. 3 – the oxirane ring and fluorine is omitted for clarity).
The tetrahydropyran ring in unrearranged products 22 and 23
adopts a conformation on the border between half-chair and
envelope (EO–5HO) while the more flexible derivative 29 adopts
a conformation somewhere between chair 1C4 and envelope
EO. All three six-membered rings in products related to the
bicyclo[2,2,2]octane skeleton (17, 19, 20, and 27) adopt almost
ideal boat conformations: B2,5 and 2,5B for 17, 19, and 20 (Fig.
3b), and B1,4 and 1,4B for 27. The tetrahydrofuran ring in products
related to bicyclo[3,2,1]octane skeleton (15, 16, and 21) adopts
envelope conformation EO and the 1,4-dioxane ring assumes
Scheme 7 Reaction of 51 with DAST.
has been suggested to explain retention of configuration during
fluorination of 3,6-dideoxyhexopyranosides 4324 (Scheme 4), and
an epi-oxonium ion comprising C1–C2–O5 has been suggested
as an intermediate in the nitrous acid deamination of benzyl 2-
amino-4,6-O-benzylidene-2-deoxy-a- and b-D-glucopyranoside.29
Participation of ring sulphur in thiofuranoid systems has also been
postulated to account for retention of configuration during DAST
fluorination.30,31 An alternative explanation of configurational
retention during fluorination of 8, 4, and 28 invokes internal
fluorine substitution SNi in a fashion similar to chlorination of
alcohols with SOCl2. Interestingly, we did not observe formation
of products arising from the ring enlargement via cleavage of
the C–C bond of the oxirane ring. This reaction course during
DAST-mediated fluorination has been documented for a number
of vicinal bicyclic epoxy alcohols.32
chair conformation O5
CO6. The products within each group differ
only in the configuration at the fluorine-bearing carbon, and the
configuration at the carbons of the oxirane ring, which remains
unchanged during the reaction. The tetrahydropyran ring in 26
adopts the boat conformation B3,O. The introduced fluorine atom
plays an active role in molecular packing of the compounds studied
as expected.34 It attracts hydrogen atoms of the oxirane ring or
another CH group proximate to the oxygen atom and forms a
weak C–H ◊ ◊ ◊ F attractive interaction. The distance varies from
Structure determination
All the starting epoxides were crystallized to produce single
crystals suitable for X-ray crystallography and the ring puck-
ering parameters33 were calculated for these structures. The
tetrahydropyran ring of 1,6:3,4-dianhydrohexopyranoses adopts
a slightly deformed version of the envelope conformation EO as
evidenced by polar projection of the ring puckering parameters10
(Fig. 2). The conformation of the tetrahydropyran ring of 1,6:2,3-
dianhydrohexopyranoses reaches the border between the envelope
conformation EO and the half-chair conformation 5HO (Fig. 2).
˚
2.40 to 2.75 A in the structures studied. This kind of intermolecular
interaction usually provides the main binding feature in one
direction of the molecular packing (see Fig. 1 in ESI†).
Fig. 3 Structural types of skeletons of fluorinated products and their
conformation in solid state as determined by X-ray analysis. The oxirane
ring, hydrogens and fluorine omitted.
The structures of the products were also characterized by
multinuclear 1D (1H, 13C and 19F) and 2D NMR spectroscopy
(COSY, HSQC). The presence and position of the fluorine atom
in the structure is demonstrated by strong geminal coupling
2J (1H, 19F) ~ 60 Hz). Those rearranged products which are
glycosyl fluorides (compounds 15–21, 27, 32, 33, and 39) show
the characteristic downfield shifted signal d = 5.30–5.83 for the
corresponding geminal proton (O–CH–F). For other fluorinated
products the geminal proton resonates at d = 4.69–5.03 except
for 38 (d = 4.17). In most cases the additional splitting due to
Fig. 2 The polar projection of the ring puckering parameters for the
starting dianhydrohexopyranoses using pseudorotation itinerary for a
general six-membered ring (E6 = EO).
The minimal variance of the ring puckering parameters within
each group of epoxides documents conformational rigidity of the
pyranose ring which is even higher than that of the corresponding
epimines.10 The absolute values of the torsion angles assumed by
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Table 2 Comparison of dihedral angles U H5–C5–C6–H6 [◦]a determined from X-ray analysis with measured and calculated coupling constants 2J [Hz]
for selected compounds
Parametera
15
16
17
19
20
27
21
22
23
26
U H5-C5-C6-H6en
U H5-C5-C6-H6ex
2J (H5, H-6en)
65.6
-59.6
0.8
2.4
0.7
68.6
-54.5
~0
63.2
-59.6
0.9
2.3
1.2
64.2
-58.0
1.2
2.4
1.2
66.2
-56.5
<1
2.8
0.8
65.9
70.8
101.9
-24.5
1.8
6.3
1.1
110.3
-16.0
2.1
7.6
1.3
94.5
-29.6
<1
4.0
0.2
-55.3
-45.2
b
b
b
2J (H5, H-6ex)
2.4
2.2
1.5
2.2
2J (H5, H-6en) calc
2J (H5, H-6ex) calc
0.6
2.5
0.5
4.0
2.7
2.3
2.5
2.9
5.9
6.0
4.0
a U H4–C4–C6–H6en/ex and 2J (H4, H6en/ex) applies for 27. b The value could not be determined.
Table 3 1H and 19F NMR chemical shifts (ppm) and signal multiplicity of fluorine-containing compounds in CDCl3
Compound H-1
H-2
H-3
H-4
H-5
H-6en
H-6ex
Other protons
19F
15
16
21
39
5.30 bd
4.19 bd
4.17 bt
4.30 m
4.31 bs
3.75 dd
3.73 d
4.30 m
4.31 bs
3.72 d
4.20 bs
4.11 dd
4.30 m
4.31 bs
3.58 d
3.95 d
3.84 dd
3.60 bd
4.27 dt
4.05 dd
4.30 m
4.23 bd
-136.4 bd
-213.6 bd
-117.0bddd
5.46 dd
5.40 bd
5.32 bd
3.84 dd
4.30 m
5.01 bd
Ts 2.48 s (3H), 7.41 m -145.6 bd
(2H), 7.85 m (2H)
-124.4 bd
17
18
19
20
32
5.67 dt
4.29ddd
3.76 ddd
3.68 m
3.50 dd
3.46 ddd
3.49 dt
3.75 t
4.44 bs
4.50 bt
4.41 ddd
4.56 bt
4.08 t
3.72 bdd
3.65 dd
4.10 bs
4.03 dd
4.15 m
4.25 bdd
3.95 dd
4.11 bs
3.66 ddd
3.85 ddd
5.66 ddd 4.27a
-122.2 bdd
5.68 bd
5.81 dd
5.83 dd
4.24 bt
4.27 ddd
4.15 m
-130.4 bd
3.56bddd 3.74 t
-120.1 bdd
3.78 bd
3.21 bd
4.15 m
Bn 4.61 d, 4.87 d,
7.37–7.39 m (5H)
Bn 4.63 d, 4.96 d,
7.38–7.39 m (5H)
-119.8 dd
-123.7 dd
33
5.55 dd
4.18 bt
4.00 ddd
4.01 m
4.29 ddd
4.29 ddd
22
23
25
29
5.66 dd
5.61 bd
5.74 d
3.64 ddd
3.01 bdt
3.52 bt
3.41 ddd
3.22 ddd
3.29 bt
5.03 ddd
4.93 bdd
4.69 d
4.54 dt
4.09 dt
4.13 dt
3.74 m
4.45 bd
3.67 dddd
3.86 dd
3.74 m
-185.7 dt
4.56 bddd
4.60 dddd
4.63 bt
-199.8 bdd
-189.6 dddd
-204.0 ddd
5.43 bdd 4.26 dd
4.66 bt
4.99 bdt
3.82 bdd
CH 5.87 s, Ph
7.41–7.70 m (5H)
24
26
27
38
5.24 d
5.64 bd
5.44 d
3.69 d
3.93 dd
5.02 dt
3.67 m
3.77 dt
4.51 d
4.89 dddd
4.83 t
5.92 dt
4.73 bd
3.91 m
4.39 bd
3.67 m
3.90 bd
4.05 dd
3.81 dd
4.21 dd
3.71 bdd
-194.7 ddd
-168.4 d
4.50 ddd
3.53 ddd
4.17 dd
4.62 ddd
2.73 bs
4.19 bd
-127.7 dp
5.50 bd
Ts 2.48 s (3H), 7.39 m -185.7 ddd
(2H), 7.84 m (2H)
a Overlap with signal of 17.
Table 4 Coupling constants nJ (H-n, H-m, Hz) of protons of fluorine-containing compounds in CDCl3
Compound 1,2 2,3 3,4
4,5
5,6en 5,6ex 6en,6ex 1,3
2,4
3,5
4,6ex 4,6en 1,6en 1,5
1,6ex Other couplings
15
16
21
39
17
18
19
20
32
33
22
23
25
29
24
26
27
38
<1 ~0
2.3 ~0
3.1
~0
<1
2.4
11.7
11.7
10.4
~0
~0
~0
~0
~0
~0
~0
<1
3.2
~0
~0
2.4
~0
~0
~0
~0
~0
~0
~0
~0
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
~0
2.2
~0
~0
~1
<1
1.2
<1
~0
~0.6 11.6
~0
~0
~0
~0
~0
~0
~0
~0
1.6 4.6 4.6
2.9
2.8
4.4
4.2
3.1
4.5
6.1
5.5
2.3
2.6
2.4
2.8
3.0
1.6b
6.3
7.6
6.7
5.4
6.8
4.0
~0
9.9
9.7
8.8
8.7
9.8
10.0
7.5
<0.5
2.0
~0
~0
<0.5
~0
<1
~1
~0
~0
a
a
a
a
a
a
a
a
2.6
4.5
1.6 3.0 4.5
3.1 3.0 4.3
3.3 1.8 8.7
1.7 1.6 8.4
2.8 4.2 3.1
1.1 3.7 ~0
~0
0
<0.5
<0.5
<1
~0
~0
~0
~0
0
~0
~0
~0
~0
~0
<1
~0
~0
<0.5
~0
~0
~0
~0
~0
1.7
1.1
2.0
0.6
~0
~0
<1
<1
a
a
a
a
~0
~0
CH2 Jgem 11.6
1.6b
1.8
2.1
0.6
<1
9.1
<1
2.1
<1
0
0
~0
1.0
<1
~0
1.4b
~0
1.4b
~0
0.6b
<1
<1
~0
0.6b
<1
~0
CH2 Jgem 11.8
~0
8.5
<0.5
~0
1.0
~0
<1
~0
a,b
3.1 3.3 <0.5 ~0
2.9 5.9 5.1
~0
5.2
4.7
3.2
2.2
1.0
7.7
11.1
6.1
9.0
8.0
<1
~0
~0
~0
~0
~0
~0
2.9 ~0
<0.5
5.0
~0
<1
~0
~0
~0
~0
1,4 <0.5
2.4 4.5 4.5
~0
~0
~0
<1
~0
~0
a
a
a
a
2.3 4.4
<1 4.6 5.3
2.2
~0
<1
~0
5.2
~0
~0
~0
~0
<1
a Not determined value, b Signals of protons H-6ex and H-6en are overlapped.
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Table 5 Coupling constants nJ (F, H-n, Hz) in CDCl3
raphy as the starting point of the geometrical optimization.35 The
calculated values of the coupling constants were then compared
with the experimental values and the final values of all proton-
proton and proton-fluorine coupling constants reported in Tables
4 and 5 were obtained by fitting to the experimental spectra.36
The type of annulation of the oxirane ring in the rearranged
products is reflected in the values of the coupling constants of
the oxirane protons: 3J = 4.3–4.6 Hz if the oxirane is annulated to
a tetrahydropyran ring (compounds 17–20, 27), or 3J = 2.9–3.2 Hz
if the oxirane is annulated to a tetrahydrofuran ring (compounds
15, 16, and 24). Coxon has observed21 a noticeable difference in the
coupling constants 3JH5,H6 and 3JH5,H6¢ in methyl 2,6:3,4-dianhydro-
a-D-altropyranoside, despite the almost identical magnitude of the
respective dihedral angles (~|60|◦). We encountered an analogous
situation in products 17, 19, 20, and 27, which possess a closely
related skeleton (derived from bicyclo[2,2,2]octane), and also in
products 15 and 16 (see Table 2 for comparison of dihedral angles
with the measured and calculated coupling constants of selected
products). The assignment of H-6en and H-6ex was therefore
made by comparison of H-6 chemical shifts and vicinal 3JH5,H6en/ex
coupling constants (or, in the case of 27, 3JH4,H6) with values
provided by DFT calculation (Table 2).
Compound H-1
H-2
3.1
H-3
1.2
H-4
H-5
H-6en H-6ex
15
16
21
39
17
18
19
20
32
33
22
23
25
29
24
26
27
38
53.2
54.6
59.4
52.2
66.1
66.8
64.4
66.4
66.4
62.3
5.6
~0
~0
~0
2.4
1.8
~0
1.2
5.3
~0
~0
a
a
a
a
a
a
a
a
a
~0
~0
~1
6.2
~0
~1.5
2.3
4.9
4.9
2.4
~0
1.1
~0
a
a
a
a
1.5
2.0
6.3
~0
~0
~0
~0
2.6
~0
~0
1.2
~0
5.8
1.4
a
a
a
~0
~0
~0
0.8b
~0
0.8b
~0
4.2
~0
~0
46.9
47.2
46.9
44.5
~0
~0
3.5
~0
5.7
12.9
5.5
~0
~0
~0
<1
2.8
~0
~0
15.1
~0
~0
~0
1.2
14.9
~0
5.7
~0
1.3
59.5
7.2
21.0
49.5
~0
~0
~0
~0
~0
~0
~0
3.9
48.1
~0
68.7
~0
3.4
~0
~0
6.9
~0
~0
a Not determined value. b Signals of H-6ex and H-6en are overlapped.
the presence of the 19F nucleus in combination with a strong
signal overlap prevented structure elucidation via analysis of the
proton coupling constants. The splitting in 13C spectra provided a
complementary assignment tool for structure elucidation in cases
where X-ray structure analysis was not available. The magnitude of
nJ (13C, 19F) corresponds to the distance from the fluorine centre in
the molecule and allows one to determine the position of oxygen
and skeleton bond branching (see Table 6). In order to obtain
correct values of proton coupling constants we applied DFT
calculations using the XYZ coordinates from X-ray crystallog-
Conclusions
We have investigated reactions of all possible 1,6:2,3-
and 1,6:3,4-dianhydrohexopytanoses with DAST. The 1,6:3,4-
dianhydrohexopyranoses reacted exclusively through skeletal rear-
rangement in which the oxygen antiperiplanar to the C2-OH bond
migrates from C1 to C2. The 1,6:2,3-dianhydrohexopyranoses
Table 6 13C NMR chemical shifts (ppm) and coupling constants nJ (19F,13C, Hz) in CDCl3
Compound
C-1
C-2
C-3
C-4
C-5
C-6
(1JF,C
)
(2JF,C
)
(3JF,C
)
(4JF,C
)
(4JF,C
)
(3JF,C
)
15
16
21
39
101.78 (231)
103.16 (215)
101.86 (220)
101.95 (226)
72.44 (24)
71.64 (25)
74.62 (25)
75.93 (25)
50.36 (10)
50.20 (~0)
62.81 (9)
67.05 (6)
49.49 (~0)
48.82 (~0)
73.20 (~0)
85.53 (2)
71.66 (1)
70.99 (2)
62.93 (2)
79.96 (2)
61.41 (1)
66.42 (3)
63.84 (1)
64.24 (~0)
(1JF,C
)
(2JF,C
)
(3JF,C
)
(4JF,C
)
(3JF,C
)
(4JF,C
)
17
18
19
20
32
33
106.24 (223)
106.71 (232)
105.56 (228)
104.33 (224)
105.48 (226)
106.13 (230)
68.20 (21)
66.99 (20)
65.71 (20)
63.68 (24)
68.16 (24)
71.03 (20)
47.03 (7)
48.34 (4)
51.27 (12)
49.20 (4)
54.29 (4)
55.17 (8)
46.25 (5)
47.26 (1)
51.29 (~0)
48.95 (~0)
71.06 (~0)
70.88 (8)
66.37 (1)
66.87 (~0)
70.37 (1)
70.25 (2)
68.39 (2)
68.33 (2)
63.60 (~0)
62.68 (~0)
67.16 (~0)
66.31 (~0)
61.62 (~0)
63.45 (~0)
(4JF,C
)
(3JF,C
)
(2JF,C
)
(1JF,C
)
(2JF,C
)
(3JF,C
)
22
23
25
29
96.89 (2)
97.07 (1)
97.44 (~0)
99.02 (2)
58.62 (2)
48.21 (~0)
54.56 (~0)
75.88 (1)
47.37 (19)
49.71 (39)
46.46 (42)
73.99 (14)
85.54 (185)
81.67 (181)
85.76 (176)
84.56 (193)
68.35 (27)
70.91 (26)
71.56 (21)
70.79 (14)
63.24 (1)
63.28 (2)
64.52 (9)
63.80 (1)
(4JF,C
)
(4JF,C
)
(3JF,C
)
(2JF,C
)
(1JF,C
)
(2JF,C
)
24
26
27
95.24 (~0)
(3JF,C
99.74 (5)
(3JF,C
91.89 (2)
(2JF,C
99.46 (32)
48.74 (~0)
(2JF,C
88.44 (17)
(4JF,C
47.96 (3)
(1JF,C
88.95 (187)
49.01 (~0)
(1JF,C
73.75 (254)
(3JF,C
45.48 (10)
(2JF,C
60.24 (28)
71.15 (23)
(2JF,C
86.79 (16)
(2JF,C
33.58 (21)
81.04 (182)
(3JF,C
75.07 (3)
(1JF,C
105.30 (221)
(4JF,C
77.12 (32)
62.34 (30)
(4JF,C
67.33 (~0)
(3JF,C
56.53 (6)
(4JF,C
66.67 (~0)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
(3JF,C
)
)
)
38
75.38 (~0)
Other carbons
29
32
33
38
CH 106.31 Ph 135.73 129.81 128.31(2) 127.61 (2)
Bn 73.39 136.92 128.61(2) 128.21 127.80(2)
Bn 73.92 137.00 128.60(2) 128.19 127.79(2)
Ts 21.73 145.81 130.27 130.27(2) 127.96(2)
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reacted predominantly by nucleophilic displacement to nonrear-
ranged products except for 2,3-alloepoxide 12 which rearranges
via migration of the C5–C6 bond. Atypical oxirane oxygen par-
ticipation was observed for 2,3-mannoepoxide 3 and an unusual
retention of configuration was observed in displacement of the C4
equatorial hydroxyl in 4, 8, and 28. In most cases the structures
of rearranged products were determined by X-ray crystallography.
DFT calculations and spectra fitting were employed to obtain the
refined values of the proton-proton and proton-fluorine coupling
constants. In most cases the rearranged products are glycosyl
fluorides which are very useful glycosyl donors.37 Nonrearranged
4-fluorohexopyranoses 22 and 23 have potential for further
functionalization through oxirane-ring opening.
Reaction of 1,6:3,4-dianhydro-b-D-altropyranose (9)
The reaction was carried out using 9 (155 mg, 1.08 mmol) and
DAST (0.6 mL, 4.54 mmol). Chromatography in S3 afforded
2,5:3,4-dianhydro-b-D-alloseptanosyl fluoride (16, 17 mg, 11%);
mp 85–87 ◦C (from ethyl acetate–light petroleum); found: C, 49.3;
H, 4.8. Calc. for C6H7O3F: C, 49.3; H, 4.8%; m/z (EI) 70 (100%),
71 (83), 69 (79), 146 (M+, 59), 97 (50). Further elution gave first
a mixture of 15 and 16 (9 mg, 6%) in 2 : 3 ratio (NMR) and then
2,5:3,4-dianhydro-a-D-alloseptanosyl fluoride (15, 65 mg, 41%);
◦
mp 115–116 C; [a]2D5 +12 (c 0.23 in CHCl3); found: C, 49.3; H,
4.8. Calc. for C6H7O3F: C, 49.3; H, 4.8%; m/z (EI) 70 (100%), 71
(85), 69 (82), 146 (M+, 54), 97 (53).
Reaction of 1,6:3,4-dianhydro-b-D-allopyranose (11)
Experimental
The reaction was carried out using 11 (150 mg, 1.04 mmol) and
DAST (0.6 mL, 4.54 mmol). Chromatography in S1 afforded an
anomeric mixture of 2,6:3,4-dianhydro-D-altropyranosyl fluorides
17 and 18 (49 mg, 32%) as a crystalline substance that could not
be resolved either by column chromatography or by crystallization
from EtOH. The ratio of b-anomer 17 and a-anomer 16 was 91 : 9
General methods
1H, 13C, COSY and gHSQC NMR spectra were measured in
CDCl3 solution at 499.9 MHz for H and at 125.7 MHz for 13C
1
measurements. The 1H and 13C NMR spectra were referenced to
the line of the solvent (CDCl3, d = 7.26 ppm and d = 76.99 ppm
respectively). The 19F NMR spectra were recorded at 282.2 MHz
and referenced to CFCl3. The NMR data are given in Tables
3–6 (compounds in tables are grouped according to structural
type – see Table 6). LRMS were recorded using EI ionization
at 70 eV, [a]2D5 values are given in 10-1 deg cm2 g-1. TLC was
carried out with Merck DC Alufolien with Kiesegel F254 and
spots were detected with an anisaldehyde solution in H2SO4. UV
detection at 254 nm was also used where appropriate. Column
chromatography was performed with silica gel 60 (70–230 mesh,
Merck). The solvents systems which were most commonly used are
denoted as S1 = ethyl acetate, S2 = ethyl acetate-light petroleum
1 : 1, S3 = ethyl acetate-light petroleum 1 : 2, S4 = ethyl acetate-
light petroleum 1 : 5. The term light petroleum refers to petroleum
fractions boiling 40–65 ◦C. The solutions were concentrated using
a vacuum rotary evaporator at less than 45 ◦C. Anhydrous sodium
sulfate was used to dry solutions during workup. Tetrahydrofuran
was dried by distillation from LiAlH4, dichloromethane was
dried by distillation from CaH2. All other chemicals were of
reagent grade and were used without purification. Synthesis of
compounds 8, 11, 12, 31, 36 and 37 is described in Supplementary
Information.
1
according to H NMR. X-Ray analysis of a crystal taken from
crystalline material obtained from EtOH allowed to determine
the structure of the major anomer 17, mp 81–84 ◦C (ethanol); m/z
(EI) 69 (100%), 59 (84), 97 (45), 115 (31), 146 (M+, 4).
Reaction of 1,6:3,4-dianhydro-b-D-galactopyranose (6)
The reaction was carried out using 6 (200 mg, 1.39 mmol)
and DAST (0.65 mL, 4.92 mmol). Chromatography in ethyl
acetate-light petroleum 1 : 3 afforded first 2,6:3,4-dianhydro-a-D-
talopyranosyl fluoride (20) with trace of an unidentified (GC-MS).
Further recrystallization f◦rom ethanol at -20 ◦C gave pure 20
(52 mg, 26%); mp 95–101 C (from ethanol); [a]2D5 +38 (c 0.36 in
CHCl3); found: C, 49.2; H, 4.8. Calc. for C6H7O3F: C, 49.3; H,
4.8%; m/z (EI) 69 (100%), 71 (82), 97 (69), 75 (33), 146 (M+, 0.1).
Further elution gave 2,6:3,4-dian◦hydro-b-D-talopyranosyl fluoride
(19, 155 mg, 52%); mp 99–100 C; [a]2D5 +43 (c 0.17 in CHCl3);
found: C, 49.3; H, 4.8. Calc. for C6H7O3F: C, 49.3; H, 4.8%; m/z
(EI) 69 (100%), 71 (80), 97 (64), 41 (60), 146 (M+, 0.2).
Reaction of 1,6:3,4-dianhydro-b-D-talopyranose (14)
The reaction was carried out using 14 (200 mg, 1.39 mmol)
and DAST (0.65 mL, 4.92 mmol). Since an initial experiment
showed that the product is sensitive to chromatography, the crude
product obtained after work-up was purified by crystallization
from ethanol to afford 2,5:3,4-dianhydr◦o-a-D-mannoseptanosyl
fluoride (21, 43 mg, 21%); mp 113–115 C (from ethanol); [a]D25
+26 (c 0.1 in CHCl3); found: C, 49.2; H, 4.8. Calc. for C6H7O3F:
C, 49.3; H, 4.8%; m/z (EI) 68 (100%), 69 (42), 71 (33), 87 (26), 97
(17), 146 (M+, 2).
General procedure for reaction of dianhydro hexopyranoses
with DAST. Neat DAST was added to a stirred suspension
of the starting dianhydro hexopyranose in CH2Cl2 (3 mL,
c(DAST) = 1.26–1.64 mmol mL-1, c(dianhydropyranose) = 0.35–
0.46 mmol mL-1) in a teflon flask under cooling (-50 ◦C). The
cooling bath was removed after 30 min and the stirring continued
for 30 h or 48 h (reaction of 3) at rt. The reaction mixture
was then diluted with CH2Cl2, cooled to -15 ◦C and methanol
(0.5 mL) was added to quench the reaction. After 30 min was the
reaction mixture washed with 1% aqueous HCl, the water phase
was saturated with NaCl and extracted with CH2Cl2 (3 ¥ 20 mL).
Combined organic layers were dried, concentrated and the residue
was chromatographed. Because the products are fairly volatile,
prolonged drying on a rotary vacuum pump should be avoided.
Reaction of 1,6:2,3-dianhydro-b-D-talopyranose (8)
The reaction was carried out using 8 (150 mg, 1.04 mmol) and
DAST (0.5 mL, 3.78 mmol). Chromatography in S3 afforded
1,6:2,3-dianhydro-4-deoxy-4-fluoro-b-D-talopyranose (22, 84 mg,
55%); mp 96–97 ◦C (from ether-light petroleum); [a]2D5 -63 (c 0.19
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in CHCl3); found: C, 49.3; H, 4.7. Calc. for C6H7O3F: C, 49.3; H,
20 min and the stirring continued for 48 h at rt. TLC in S2 indicated
absence of the starting 28. The reaction mixture was worked-up as
described in general procedure for reaction with DAST except that
water was used instead of 1% aqueous HCl. Chromatography in
S3 afforded first crystalline 1,6-anhydro-2,3-di-O-benzylidene-4-
deoxy-4-fluoro-b-D-talopyranose (29, 89 mg) which contained 9%
of an unknown fluorine-containing product according to NMR.
Recrystallization from ethanol gave pure 29 (53 mg, 32%), mp
4.8%; m/z (EI) 99 (100%), 59 (18), 72 (15), 75 (12), 146 (M+, 0.1).
Reaction of 1,6:2,3-dianhydro-b-D-gulopyranose (4)
The reaction was carried out using 4 (200 mg, 1.39 mmol) and
DAST (0.6 mL, 4.54 mmol). Chromatography in ethyl acetate -
light petroleum 1 : 7 afforded 1,6:2,3-dianhydro-4-deoxy-4- fluoro-
b-D-gulopyranose (23, 125 mg, 61%); mp 73–75 ◦C (from ethanol);
[a]2D5 +42 (c 0.1 in CHCl3); found: C, 49.4; H, 4.8. Calc. for
C6H7O3F: C, 49.3; H, 4.8%; m/z (EI) 99 (100%), 59 (19), 72 (14),
75 (11), 146 (M+, 0.2). Further elution gave first a mixture of 23
and 24 (29 mg, 15%) in ratio 1 : 17 by GC-MS, then syrupy 1,6:2,3-
dianhydro-5-deoxy-5-fluoro-a-L-talofuranose (24) (52 mg, 26%),
found: C, 49.5; H, 4.9. Calc. for C6H7O3F: C, 49.3; H, 4.8%; m/z
(EI) 88 (100%), 71 (46), 59 (45), 99 (27), 146 (M+, 0.4).
◦
109–112 C, [a]2D5 -56 (c 0.20 in CHCl3); found: C, 61.8; H, 5.2.
Calc. for C13H13O4F: C, 61.9; H, 5.2%. Further elution afforded
the unreacted 28 (9 mg, 5%).
Reaction of 31 with DAST. A solution of 31 (200 mg,
0.72 mmol) in dichloromethane (1.5 mL) was added to a solution
of DAST (0.35 mL, 2.65 mmol) in dichloromethane (2.0 mL)
under cooling (–50 ◦C) and stirring. The cooling bath was removed
after 20 min and the stirring continued for 24 h at rt. TLC in
S2 indicated absence of the starting 31. The reaction mixture
was worked-up as described in general procedure for reaction
with DAST. Chromatography in. S4 afforded first syrupy 2,6-
anhydro-3-azido-3-deoxy-4-O-benzyl-a-D-talopyranosyl fluoride
(32, 69 mg, 34%), [a]2D5 -135 (c 0.44 in CHCl3); found: C, 56.05; H,
5.1; N, 14.7. Calc. for C13H14O3N3: C, 55.9; H, 5.05; N, 15.05%.
Further elution afforded syrupy 2,6-anhydro-3-azido-3-deoxy-4-
O-benzyl-b-D-talopyranosyl fluoride (33, 92 mg, 46%), [a]2D5 -108
(c 0.27 in CHCl3); found: C, 56.2; H, 5.1; N, 14.5. Calc. for
C13H14O3N3: C, 55.9; H, 5.05; N, 15.05%.
Reaction of 1,6:2,3-dianhydro-b-D-mannopyranose (3)
The reaction was carried out using 3 (200 mg, 1.39 mmol)
and DAST (0.6 mL, 4.54 mmol). Chromatography in S3 gave
first an inseparable mixture of 1,6:2,3-dianhydro-4-deoxy-4-
fluoro-b-D-talopyranose and 1,6:2,3-dianhydro-4-deoxy-4-fluoro-
b-D-mannopyranose (22 and 25, 107 mg, 52%), the ratio of 22 and
1
25 was 21 : 4 according to H NMR, the NMR spectrum of the
major product 22 was identical with that of the product prepared
from 8. The epimers 22 and 25 were also inseparable by GC-
MS. Further elution gave 1,6:2,4-dianhydro-3-deoxy-3-fluoro-b-
D-idopyranose (26, 24 mg, 12%) contaminated with impurities
(GC-MS), recrystallization fromethylacetate-light petroleum gave
pure 26 (19 mg, 9%) mp 110 ◦C, found: C, 49.4; H, 4.85. Calc. for
C6H7O3F: C, 49.3; H, 4.8%; m/z (EI) 72 (100%), 59 (75), 116 (15),
40 (6).
Acknowledgements
The service of the X-ray diffractometer was supported by the
Ministry of Education (Grant Nos. MSM0021620857. NMR
measurements were supported by the Grant Agency of ASCR,
Grant No. IAA400720706.
Reaction of 1,6:2,3-dianhydro-b-D-allopyranose (12)
Notes and references
The reaction was carried out using 12 (200 mg, 1.39 mmol)
and DAST (0.6 mL, 4.54 mmol). Chromatography in
S3 gave (5R)-1,41:2,3-dianhydro-4-deoxy-4-C-hydroxymethyl-D-
lyxo-pentodialdo-1,5-pyranosid-5-yl fluoride (27, 34 mg, 17%),
mp 83–92 ◦C, found: C, 49.3; H, 4.8. Calc. for C6H7O3F: C, 49.3;
H, 4.8%; m/z (EI) 69 (100%), 87 (46), 100 (42), 115 (3). Further
elution gave the starting dianhydro derivative 12 (10 mg, 5%).
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Reaction of 37 with DAST. The reaction was carried out using
37 (150 mg, 0.44 mmol) and DAST (0.5 mL, 3.78 mmol). Chro-
matography in ethyl acetate-light petroleum 1 : 7 afforded 116 mg
(77%) of a mixture of 1,6-anhydro-3-azido-2,3-dideoxy-2-fluoro-
4-O-tosyl-b-D-glucopyranose (38) and 2,5-dianhydro-3-azido-3-
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phase HPLC of a sample of the mixture (7 mg) in acetonitrile-water
1 : 1 afforded pure syrupy 38 (4 mg), nmax(film)/cm-1 2098(N3),
HREIMS: m/z 366.05295 calcd. for C13H14O5FN3SNa: 366.05304.
Compound 39 was obtained only as an enriched HPLC fraction
(in cca 73% purity)
Reaction of 28 with DAST. A solution of 2817 (166 mg,
0.66 mmol) in dichloromethane (2.0 mL) was added to a solution
of DAST (0.35 mL, 2.65 mmol) in dichloromethane (2.0 mL) under
cooling (-50 ◦C) and stirring. The cooling bath was removed after
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