A practical and scalable synthesis of carbohydrate based oxepines

Article abstract of DOI:10.1039/c6ob00262e

An efficient, seven-step synthesis of carbohydrate based oxepines is reported using per-O-acetyl septanoses as key intermediates. The scope of the synthesis was evaluated by varying both the pyranose starting materials and protecting groups incorporated into the oxepine products. The practicality of the method make it amenable to scale up as demonstrated by the gram-scale synthesis of the d-glucose derived oxepine.

Full text of DOI:10.1039/c6ob00262e

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A practical and scalable synthesis of carbohydrate based oxepines
Raghu Vannama and Mark W. Peczuha*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient, seven-step synthesis of carbohydrate based oxepines is reported using per-O-acetyl septanoses as key intermediates. The
scope of the synthesis was evaluated by varying both the pyranose starting materials and protecting groups incorporated into the
oxepine products. The practicality of the method make it amenable to scale up as demonstrated by the gram-scale synthesis of the
glucose derived oxepine.
D-
Introduction
Carbohydrate based oxepines (oxepines)1 are ring-expanded They include the ring closing metathesis of dienes,10,13
glycals (e.g., vs sequential
1
2
in Fig. 1).2 Glycals are six-membered cyclic cycloisomerization of alkynols,11,12,14 and
a
enol ethers with a lengthy track record as starting materials for cyclization and elimination of hydroxy acetals.15,16 These
oligosaccharides3 and as building blocks in small molecule syntheses have some drawbacks, however, such as using
target synthesis (e.g., natural products).4 Their value in these expensive catalysts, intricate reaction protocols, low efficiency,
roles comes from the enol ether functionality and the and limited protecting group scope. The desire to utilize
stereogenic centers; oxidation, addition, and rearrangement oxepines in synthesis and the shortcomings of the current
reactions deliver useful intermediates en route to individual methods for their preparation prompted us to search for a
targets. Likewise, oxepines have played a key role in the practical alternative. Here we report a simple, seven-step
synthesis of seven-membered ring carbohydrates, called route for the synthesis of per-O-actetyl protected
septanoses.5,6,7 Our overarching strategy for septanose carbohydrate based oxepines that is scalable. Akin to their
synthesis has been to apply methods established for the glycal congeners, we expect that these compounds will serve
formation of pyranosyl glycosides to septanose glycosylations.8 as valuable starting materials in the synthesis of a variety of
For example, DMDO epoxidation of oxepines resulted in the target molecules.
formation of 1,2-anhydroseptanoses, which were then opened
with a variety of nucleophiles to give the corresponding
septanosyl derivatives.9,10 Due to their use as starting
materials, carbohydrate based oxepines have become
important synthetic targets in their own right.8,11,12 If oxepines
are to be used as ring expanded glycals in other contexts, the
current limitation of ready access to this class of compounds
must be overcome.
OAc
OAc
O
O
AcO
AcO
AcO
AcO
AcO
2
1
OP
OAc
O
O
Several methods for the preparation of glycals have been co-
opted towards the synthesis of carbohydrate based oxepines.
PO
PO
AcO
AcO
X
OH
OP
AcO
OAc
5
3
4
X = Br
X = OAc
Fig. 1 Retrosynthetic analysis of oxepine using key intermediate
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Glycals have traditionally been synthesized via a reductive and the mixture of anomers. Quantifying the ratio of these
elimination of acetylated glycosyl bromides using elemental isomers was consequently difficult. The 13C spectrum of
9
zinc in acetic acid (Fischer-Zach method).17,18 Over the years suggested, however, that each C2 stereoisomer existed
the route has been modified in terms of reducing agents used primarily as one anomer.23 Hydrogenolysis of the benzyl
or the leaving groups on the anomeric carbon. Nonetheless, groups was a crucial step in this synthesis. Some standard
due to its efficiency, affordability and low toxicity, the Fischer- catalyst-solvent combinations to conduct the reaction were
Zach method is used to synthesize glycals on a multi-kilogram unsuccessful.24,25 To our delight, however, we found that
scale.19 These attributes led us towards the development of a hydrogen and 10% Pd/C in THF proved to be an effective
reductive elimination approach for the synthesis of oxepines combination for the reaction. Debenzylation was followed by
(e.g.,conversion of
3
to
1
in Fig. 1).
acetylation, providing per-O-acetyl septanoses 4 in 80% yield
over two steps. The per-O-acetyl compounds were isolated as
vinylation
OH
OBn
a mixture of four diastereomers, based on the possible
OBn
BnO
BnO
O
THF
MgBr,
configurations at both C1 and C2. The fact that
4 existed as a
BnO
BnO
OH
X
0 °C to rt
mixture of four diastereomers was of little concern because
their stereogenicity would be removed in the reductive
OH
OBn
OBn
dr 3:2
82%
6
elimination step when forming oxepines such as
1. The per-O-
7 X = CH2
8 X = O
O3; PPh3
ozonolysis
-78 °C to rt
acetylseptanoses themselves (e.g., 4) are useful starting
91%
materials for the synthesis of novel septanose glycoconjugates.
5 steps
50%
acetylation
Overall, the five-step route to the per-O-acetylseptanoses was
Ac2O, pyr., DMAP
DCM
simple and efficient and afforded the septanose
from the pyranose
The five-step route, established with
towards the preparation of per-O-acetylseptanoses starting from
xylose 10, -mannose 15, and -galactose 20 to probe the generality
4 in 50% yield
0 °C to rt
6.
84%
D
-glucose, was applied
OAc
debenzylation
D-
OBn
OAc
OAc
O
OAc
C1
AcO
AcO
O
1) Pd/C, H2, THF, rt
BnO
BnO
D
D
per-acetylation
of the approach (Fig. 2). Whereas the diastereoselectivity of vinyl
addition to benzyl protected pyranose lactols is known for glucose,
galactose, and mannose, the selectivity for addition to xylose has
not been reported, to the best of our knowledge. In the case of the
former examples, the diastereomeric mixtures of allylic alcohol
products 7, 16, and 21 (Scheme 1 and Fig. 2) reflected the values
previously reported in the literature. For xylose, the formation of
AcO
C2
BnO
2) Ac2O, pyr., DMAP
OAc
DCM
0 °C to rt
dr ~ 2:2:1:1
80% (2 steps)
9
4
Scheme 1 Synthesis of D-glucose derived per-O-acetylseptanose.
the
R configuration at C2 was preferred, being the major
diastereomer in a 10:1 ratio. This diastereomer was likely preferred
based on Cram-chelate model. Following the same sequence
depicted in Scheme 1, the per-O-acetylseptanoses derived from
xylose and mannose, 13 (34%, five steps) and 18 (57%, five steps),
respectively, largely proceeded without incident (Fig. 2). Their 13C
NMR spectra were complex because mixtures of stereoisomers (C1
and C2) were being carried through the sequence but they were,
nonetheless, similar to those observed previously in the glucose
series, including the preference for one anomeric configuration for
each C2 stereoisomer, as was observed for 9.
Results and discussion
Synthesis of per-O-acteylseptanoses
Our investigation began with the development of a five-step
route to per-O-acetyl septanoses as illustrated in Scheme 1
using 2,3,4,6-tetra-O-benzyl
D-glucose 6 as starting material. It
should be noted that 6 is commercially available, although
somewhat expensive. Nonetheless we have considered it the
starting material for synthesis; the per-O-benzyl lactols have
systematically been considered the starting materials for our
synthesis for ease of comparison. We appreciate that these
lactols are not uniformly available and that places a limitation
on the practicality of the method described here.
In the galactose series, however, there were extra signals in the
acetal region of the 13C NMR23 spectra of the material that came
about from hydrogenolysis and per-acetylation of di-O-
acetylseptanose 22 (Fig. 2). The data suggested that more than the
standard four isomers of this compound were present in the
mixtures. Our explanation for this observation relied on our
characterization of the oxepines that arose in this series as
described in the proximal section. We propose that 24 came
about via migration of the acetyl group from C1 to C3 and
subsequent equilibration of the resulting septanose to a
pyranose during the debenzylation step (Fig. 3) of the
hydrogenolysis/per-acetylation sequence. Formation of 24 is
yet another example of rearrangements that occur with seven
membered ring sugars.5,22
Vinylmagnesium bromide addition to
diastereomeric mixture of allylic alcohols
6
gave
a
3:2
7
in 82% yield.20,21
Without separating the diastereomers, the alkene moiety of
was cleaved via ozonolysis giving hydroxy-aldehydes (91%).
As had been reported previously, was in equilibrium with the
7
8
8
seven-membered ring hemiacetal as observed by NMR
spectroscopy.21,22 To avoid isomerization of the α-hydroxy
aldehyde to the corresponding hydroxymethyl ketone,23
8
was
directly acetylated to trap it in its cyclic form, providing di-O-
acetyl-tetra-O-benzyl septanoses in 84% yield. Di-O-acetyl
septanoses were a relatively complex mixture based on the
9
9
ratio of stereoisomers at C2 (based on vinyl Grignard addition)
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Formation of oxepines via reductive elimination
AcOH gave a pair of diastereomeric α-septanosyl bromides 3
differing only in their configuration at C2.26 By 13C NMR, only
two signals for anomeric carbons (C1), at 87 and 84 ppm, were
Anomeric acetates are useful precursors for the introduction
of other leaving groups at the C1 position under acidic
conditions. Treatment of per-O-acetylseptanoses
4 with HBr in
Fig. 2. Starting materials, intermediates and oxepines of xylose, mannose and galactose series
.
conditions (Table 1, Entry 1). Oxepine
1 was obtained in 45%
yield over two steps under these conditions. NMR analysis
allowed the assignment of all the protons H1-H7 and
Table 1. Conversion of per-O-acetyl septanose to oxepine via bromination and
reductive elimination.
corresponding carbons C1-C7 of oxepine
1. Further, HMBC
spectra contained a diagnostic cross peak between C6 and H1
confirming the oxepine structure.23 We also evaluated other
reductive elimination conditions reported for glycal formation.
Using a zinc-copper couple27 (Entry 2) provided
under neutral conditions28 (Entry 3)
was obtained in 44%
yield. We next tried zinc in the presence of a catalytic amount
1 in 42% yield;
1
29
of vitamin B12 (Entry 4), which yielded only 31% of
Reductive elimination with Cp2TiCl2 following Schwartz
conditions30 (Entry 5) gave
in higher yield (64%). Despite its
1.
Entry Conditions
Yielda
1
2
Zn, AcOH:H2O, Et2O, 0 °C to rt,12 h
45%
42%
1
higher yield, we considered the reaction protocols required to
generate Ti(III) to be cumbersome for the gain in yield. We
opted for the traditional Fischer-Zach protocol in subsequent
syntheses because of its balance of yield and ease of
execution.
Zn, CuSO4, NaOAc, AcOH:H2O, Et2O,
0 °C to rt, 10 h
3
4
Zn, NaH2PO4, acetone, rt, 6 h
Zn, vitamin B12, NH4Cl, MeOH, rt, 1 h
Zn, Cp2TiCl2, CaH2, dioxane, rt, 1 h
44%
31%
64%
5
We next endeavored to convert each of the other per-O-
acetyl species to their corresponding oxepines by bromination
and reductive elimination. Compounds 14 and 19 in the xylose
and mannose series, respectively, were made in 35% and 48%
by the two-step sequence (Fig. 2). When the per-O-acetyl
mixture from the galactose series was treated to the same
conditions, a 1:1 mixture of products was obtained in a
combined yield of 55%. The same products also arose under
aYields reported are after two steps from 4.
observed. With the anomeric bromides in hand, we subjected
them to standard Fischer-Zach reductive elimination
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mild and neutral reductive elimination conditions, albeit in reaction. Nonetheless, these investigations led us to believe
variable yields (46% and 52%).23 Characterization of the that this synthetic sequence is viable for protecting group
products revealed that one was the expected oxepine, 25 diversification.
(28%). The other product (27%) was assigned structure 26
through analysis of NMR spectra of the compound, particularly
Scheme 2. Synthesis of benzoyl and acetonide protected oxepines
through a C5-H1 correlation in the HMBC spectrum. The
structure of product 26 and the peculiarities in the NMR
spectra of the per-O-acetyl species mentioned above
confirmed that 24 was likely the precursor to 26. We propose
that 24 came about via migration of the C1 acetyl group to C3
and subsequent re-equilibration of the resulting septanose to
a
pyranose during the debenzylation, per-acetylation
sequence.
Scaled up synthesis of oxepine 1
We also sought to develop a scalable synthesis of oxepines in
order to improve the low to medium throughput of material
that can be prepared by RCM of enol ethers.13 We scaled up
the synthesis of oxepine
We began the scaled up synthesis with 20 g of tetra-O-benzyl-
-glucopyranose . The Grignard addition step went in 91%
yield to give intermediate . We then took half of the product
material from the Grignard reaction (approximately 10 g) and
completed the synthesis through to . Due to safety concerns,
we capped the scale of the ozonolysis reactions at two 5 g
batches, obtaining in 80% combined yield. Acetylation of the
resulting diol gave di-O-acetate in 87% yield. Debenzylation
1 to illustrate the method (Scheme 3).
D
6
7
1
Fig. 3. Proposed mechanism of intramolecular acetate transfer during
debenzylation reaction in the galactose series
8
9
and per-acetylation was straightforward, although the
hydrogenolyis of benzyl ethers was run at greater catalyst
loading (35 wt% of 10% Pd/C relative to 20 wt%) that was used
To expand the scope of the method, we modified the
synthetic sequence to incorporate different protecting groups
into the oxepine. A logical place to change protecting groups
was at the 1,2-di-O-acetyl septanose that arose from
hydrogenolysis (e.g., 17 in Scheme 2). Benzoylation of the free
on smaller scale. Subsequent per-acetylation gave
4 in 80%
yield over two steps. Anomeric bromide formation and
reductive elimination (using Fischer-Zach conditions) of per-O-
acetyl septanoses yielded 70% of oxepine 1. Total yield over
hydroxyls of 31 gave 32 in 85% yield; subsequent bromination
and reductive elimination resulted in per-O-benzoyl oxepine
33 in 55% yield after two steps. Likewise, acetonide protection
of 31 gave 34 (64%). To avoid cleavage of the acid-labile
acetonide groups on 34, we chose TMS bromination and
Schwartz reductive elimination conditions in this series.
Bromination of 34 with TMSBr followed by reductive
elimination with Ti(III) gave 20% yield of oxepine 35. The
inefficiency of the reaction may be attributed to other
eliminations that were possible during the course of the
the seven-step sequence was 35% from the pyranose, greater
than 85% average yield per step. The method has allowed the
preparation of oxepine
1 on a multi-gram scale, where 10 g of
allylic alcohol 7 was converted to >2.5 g of oxepine
1.
Moreover, it is anticipated that yields could be further
optimized when the synthesis is conducted on even larger
scale.
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Ozonolyis: To a long neck round bottom flask having both an
inlet and outlet was added 1,3,4,5-tetrakis(benzyloxy)oct-7-
ene-2,6-diol (2.00 g, 3.50 mmol, 1 eq.) in DCM (30 mL/g of
starting material). The solution was cooled to -78 °C, ozone gas
was bubbled through the reaction mixture by using WELSBACH
instrument until a dark blue color persisted. Upon the
appearance of the blue color, ozone generation was ceased
and the reaction mixture was purged with oxygen gas until the
reaction mixture became clear and colorless once again. Still at
-78 °C, a solution of triphenylphosphine (2x mass of starting
material) in DCM (2 mL/g of PPh3) was added drop-wise to the
reaction mixture. It was allowed to stir as it warmed to rt over
14 h. After, the solvents were concentrated under reduced
pressure and the residue was purified by column
chromatography using hexanes: ethyl acetate as a solvent
system to give respective hydroxyaldehyde as colorless oil (75 -
91%).
2) ozonolysis
5 g
4) debenzylation
80%
7
9
4
3) acetylation
5) per-acetyaltion
6) bromination
10 g
10 g
7) red. elimination
87%
80% (2 steps)
1) vinylation
20 g
5 g
70% (2 step)
91%
OBn
O
OAc
O
AcO
AcO
BnO
BnO
OH
AcO
OBn
seven steps
6
1
35%
Acetylation: To a solution of hydroxyaldehyde (3.00 g, 5.20
mmol, 1 eq.) in DCM (10 mL/g starting material) was added
pyridine (4 mL/g starting material) and a catalytic amount of
N,N-dimethylaminopyridine (DMAP) (10 mol%). To this mixture
was added acetic anhydride (7.2 mL/g of starting material) was
added drop by drop at 0 °C. After completion of the reaction
(~12 h), ice-cold water (10 mL/g of starting material) was
added into the flask. The reaction mixture was extracted with
DCM (2 x 30 mL/g of starting material). The solvents were
evaporated under reduced pressure and purified by column
chromatography using hexane:ethyl acetate as a solvent
system to give respective di-O-acetyl-tetra-O-benzyl
septanoses (80 - 90%).
Scheme 3. Scaled-up synthesis of oxepine 1
Conclusions
In conclusion we have developed a simple, seven step route
to the synthesis of per-O-acetyl oxepines from pyranoses that
is readily scalable. The sequential bromination and reductive
elimination reactions were successfully applied to synthesize
novel oxepines from per-O-acetyl septanoses. Interestingly,
the per-O-acetyl septanoses are likely valuable intermediates
in their own right. Our method also allows the synthesis of
oxepines with the different protecting groups. Applications
and reactions of the new oxepines as well as the per-O-acetyl
septanose intermediates will be reported in due course.
The NSF partially supported this work through a grant to
MWP (CHE- 1506567).
Hydrogenolysis/Acetylation (Procedure 3)
To the di-O-acetyl-tetra-O-benzyl septanoses (1.00 g, 1.50
mmol, 1 eq.) dissolved in THF (20 mL/g starting material), was
added 20% weight of 10% Pd/C (0.20 g) and the mixture was
stirred for 12 h at rt under an atmosphere of hydrogen gas.
The solution was then filtered through celite, washed with
excess methanol and the combined filtrates were
concentrated under reduced pressure. After TLC analysis
showing the absence of starting material and no UV active
spots, the crude reaction mixture was then dissolved in
pyridine (5 mL/g starting material), and acetic anhydride (7.2
mL/g) was added at 0 °C and stirred it for 6 h at rt. The mixture
was concentrated under reduced pressure and purified by
column chromatography using hexane: ethyl acetate as solvent
system to give the respective per-O-acetyl septanoses (80 -
85%).
Experimental Section
Vinylation (Procedure 1)
To a round bottom flask containing 2,3,4,6-tetra-O-benzyl D-
pyranose (5.00 g, 9.25 mmol, 1 eq.) in THF (6 mL/g pyranose)
was added 0.7M in THF of vinylmagnesium bromide (46.3
mmol, 5 eq.) slowly (7 mL/min) at 0 °C. The reaction mixture
was allowed to warm to rt and was allowed to stir for 20-24 h.
After, sat. NH4Cl (10 mL/g of starting material) was added to
the reaction mixture at 0 °C to quench it. The mixture was
extracted with ethyl acetate (3 x 25 mL/g of starting material).
The organic layer was dried over Na2SO4 and the solvent was
removed under reduced pressure. The residue was purified by
column chromatography using hexanes:ethyl acetate as a
Glycosyl Bromide Formation (Procedure 4)
To a solution of per-O-acetyl septanose (0.50 g, 1.1 mmol, 1
eq.) in DCM (5 mL) was added a 30% HBr in acetic acid (2.5 mL)
solution at 0 °C. After complete consumption of per-O-acetate
derivative (usually ~12 h) as observed by TLC (Rf 0.4, 5:2
hexane:ethyl acetate) the resulting solution was poured
directly into a 100 mL beaker half full of ice. Additional DCM
was added to this mixture and it was then transferred to a
solvent
system
to
give
respective
1,3,4,5-
tetrakis(benzyloxy)oct-7-ene-2,6-diol (70 - 91%).
Ozonolysis and Acetylation (Procedure 2)
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separatory funnel. The water was removed and the organic hexane:ethyl acetate). The solution was then filtered through
phase was washed with cold sat. NaHCO3 (2 x 40 mL), water celite and the filter was washed using excess methanol (5 mL).
(40 mL) and brine (40 mL) and dried with Na2SO4. The solvents Solvent was evaporated from the filtrate under reduced
were removed under reduced pressure to give the respective pressure to give crude product, which was redissolved in DCM
septanosyl bromide.
(15 mL) and washed with H2O (10 mL) and brine (10 mL). The
organic layer was dried with Na2SO4, evaporated under
reduced pressure and the residue was purified by column
chromatography using hexane:ethyl acetate as solvent system
Reductive Elimination Reactions (Procedure 5)
(A) Zn, 1:1 AcOH: H2O, diethyl ether, 0 °C to rt, 12 h
A solution of septanosyl bromide (0.50 g, 1.03 mmol, 1 eq.) in to give per-O-acetyl oxepine.
diethyl ether (7.5 mL) was quickly added to the flask having 1:1
H2O: AcOH (10 mL) and Zn (0.470 g, 7.1 mmol, 7 eq.) at 0 °C. (E) Zn, Cp2TiCl2, CaH2, dioxane, rt, 1 h
The mixture was allowed to warm to rt and the reaction To a 100-mL Schlenk round bottom flask, were added Cp2TiCl2
continued for 12 h. The reaction mixture was then filtered (0.298 g, 1.2 mmol, 3 eq.), Zn (0.156 g, 2.4 mmol, 6 eq.), CaH2
through a short pad of celite and more diethyl ether (15 mL) (0.01 g as trace moisture scavenger), and dioxane (4 mL). The
was added to rinse the filtered material. The combined flask was degassed by freeze–pump–thaw cycles and was filled
filtrates were washed with H2O (10 mL), sat. NaHCO3 (10 mL), with N2 (three times). The reduction occurred in less than 5
brine (10 mL) and then dried with Na2SO4. Solvent was min. To this solution septanosyl bromide (0.2 g, 0.41 mmol, 1
removed under reduced pressure and the residue was purified eq.) in THF (1 mL) was added dropwise at rt. After 1 h, the
by column chromatography using hexane:ethyl acetate as resulting solution was evaporated under reduced pressure and
solvent to give the respective per-O-acetyl oxepine. Note that the residue was purified by column chromatography using
in the glucose series, multiple reactions were performed hexane:ethyl acetate as solvent system to give per-O-acetyl
ranging scale 0.05 g to 5.00 g.
oxepine.
(B) Zn, CuSO4, NaOAc, 1:1 AcOH: H2O, diethylether, 0 °C to rt, Compound 9. Obtained as colorless oil in 76% yield after two
10 h steps using as starting material following general procedure-
7
Septanosyl bromide (0.10 g, 0.021 mmol, 1 eq.) in diethyl ether 2. Rf 0.4 (5:1 Hex:EtOAc); 1HNMR (400 MHz, CDCl3) δ 7.43-7.25
(0.5 mL) was added to a solution of Zn (0.076 g, 1.17 mmol, 5.6 (m, 74H), 6.15-6.06 (m, 2.5H), 5.80 (d, J= 5.1 Hz, 0.6H), 5.54-
eq.), NaOAc (0.074 g, 0.9 mmol, 4.3 eq.), CuSO4 (0.002 g, 0.012 5.38 (m, 2.7H), 5.20-5.02 (m, 2.5H), 5.20-4.28 (m, 33H), 4.19-
mmol, 0.06 eq.) in 1:1 AcOH: H2O (0.4 mL) at 0 °C. The 3.59 (m, 20H), 2.27 (s, 1.6H), 2.17 (s, 3.4H), 2.10 (s, 4.2H), 1.96-
resulting solution was stirred for 6 h at rt, then it was filtered 1.95 (m, 4.7H), 1.94 (s, 3.3H); 13CNMR (100 MHz, CDCl3) δ
through a short pad of celite and washed with excess of diethyl 170.2, 169.9 (2), 169.8, 169.7, 169.2, 139.0, 138.7, 138.6, 138.4
ether (15 mL). The combined filtrates were washed with (2), 138.3, 138.2, 138.1, 137.9, 137.7, 128.7 (2), 128.6 (2),
NaHCO3 (5 mL), H2O (5 mL), dried with Na2SO4, and 128.5, 128.4, 128.3, 128.2, 128.1 (2), 128.0 (2), 127.8 (2),
concentrated under reduced pressure. The residue was 127.2, 95.5, 93.7, 89.8, 88.3, 84.4, 81.0, 80.4, 80.0, 78.9, 78.4,
purified by column chromatography using hexane: ethyl 78.1, 77.1, 76.8, 76.7, 76.3, 76.1, 75.7, 75.4, 75.3, 75.1, 74.8,
acetate as solvent system to give per-O-acetyl oxepine.
73.8, 73.5, 73.4, 72.9, 72.7, 72.6, 72.2, 71.7, 71.4, 70.7, 70.5,
70.3, 21.4, 21.3, 21.2, 21.0 (2); TOF HRMS (DART) m/z calcd for
C39H46O9N (M+NH4)+ 672.3173, found 672.3170.
(C) Zn, NaH2PO4, acetone, rt, 6 h
To a solution of septanosyl bromide (0.095 g, 0.20 mmol, 1
eq.) in acetone (0.25 mL) was added saturated NaH2PO4 (0.5 Compound 4. Obtained as thick colorless oil in 80% yield from
mL) and Zn dust (0.162 g, 2.5 mmol, 12.5 eq.) at rt. The after two steps using general procedure-3. Rf 0.45 (1:1
resulting mixture was stirred for 10
at the same Hex:EtOAc); 1HNMR (400 MHz, CDCl3) δ 6.20 (d, J = 1.1 Hz,
9
h
temperature. After, the solution was extracted with EtOAc (2 0.5H), 6.11-6.10 (d, J = 4.7 Hz, 0.6H), 6.02 (d, J = 1.0 Hz, 0.1H),
x10 mL). The organic phase was washed with H2O (10 mL), 5.92-5.90 (d, J = 7.0 Hz, 1H), 5.83 (d, J = 1.0 Hz, 0.3H), 5.72-5.71
NaHCO3 (10 mL) brine (10 mL), dried over Na2SO4 and (d, J = 6.9 Hz, 0.8H), 5.55-5.47 (m, 1.5H), 5.38-5.11 (m, 10H),
concentrated. The residue was purified by column 5.00-4.93 (m, 4H), 4.45-4.42 (m, 0.7H), 4.27- 4.17(m, 2.2H),
chromatography using hexane:ethyl acetate as solvent system 4.10-3.85 (m, 8H), 2.17 (s, 2.2H), 2.03-1.89 (m, 58H); 13CNMR
to give per-O-acetyl oxepine.
(100 MHz, CDCl3) δ 170.6, 170.3, 170.2, 169.9, 169.7, 169.5,
169.4, 169.3, 169.2, 169.1, 168.9, 169.8, 168.7, 168.5, 95.7,
95.1, 95.0, 93.2, 92.7, 88.7, 80.5, 77.3, 75.3, 74.1, 72.0, 71.6,
(D) Zn, vitamin B12, NH4Cl, MeOH, rt, 1 h
To a solution of vitamin B12 (0.0037 g, 1 mol%) in methanol (1 71.4, 71.2,71.0, 70.4, 70.3, 69.9, 69.3, 69.2, 69.0, 68.9, 68.8,
mL) were added Zn (0.275 g, 4.2 mmol, 15 eq.) and NH4Cl 68.7, 68.6, 68.4, 67.4, 63.4, 63.3, 63.2, 62.9, 61.3, 60.2, 27.6,
(0.224 g, 4.2 mmol, 15 eq.) respectively, at rt. The resulting 22.1, 20.9, 20.8, 20.7, 20.5, 20.3, 20.2, 20.1; TOF HRMS (DART)
mixture was stirred for 0.5 h and then septanosyl bromide m/z calcd for C19H30O8N (M+NH4)+ 480.1717, found 480.1715.
(0.130 g, 0.28 mmol, 1 eq.) in methanol (1 mL) was then added
to the reaction mixture. TLC was performed after 10 min, Compound 3. Obtained as colorless oil using general
which showed completion of the reaction (product Rf 0.45 5:2 procedure-4 starting from 4; this material was characterized
6 | J. Name., 2012, 00, 1-3
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but not routinely isolated. Rf 0.5 (1:1 Hex:EtOAc); HNMR (400 63.1, 21.1, 20.9 (2), 20.8; TOF HRMS (DART) m/z calcd for
MHz, CDCl3) δ 6.43 (d, J= 4.6 Hz, 4H), 6.07 (d, J = 8.3 Hz, 5H), C15H24O9N (M+NH4)+ 362.1451, found 362.1455.
5.62-5.50 (m, 16H), 5.39-4.98 (m, 52H), 4.52-4.47 (m, 5H),
4.34-4.30 (m, 8H), 4.22-4.16 (m, 15H), 4.09-3.95 (m, 27H), Compound 26. Rf 0.45 (5:2 Hex: EtOAc); [α]D -203.7 (c 0.25,
2.04-1.92 (m, 183H); 13CNMR (100 MHz, CDCl3) δ 170.8, 169.9, CHCl3); 1HNMR (400 MHz, CDCl3) δ 6.45(dd, J = 6.0, 1.2 Hz, 1H),
169.4, 169.0, 168.3, 87.0, 84.5, 74.4, 73.5, 73.0, 71.9, 71.4, 5.53- 5.50 (ddd, J = 1.8, 1.8, 7.2 Hz, 1H), 5.41 (m, 1H), 5.30-5.26
70.0, 69.5, 68.5, 62.3, 60.6, 21.2, 20.9, 20.7, 20.5, 20.4.
(dd, J = 9.8, 7.2 Hz, 1H), 4.82 (dd, J = 6.0, 2.5 Hz, 1H), 4.40-4.36
(dd, J = 11.8, 4.8 Hz, 1H), 4.25-4.19 (m, 2H), 2.20-2.04 (m, 20H);
Compound 1. Obtained as colorless oil in 40-70% yield (two 13CNMR (100 MHz, CDCl3) δ 170.9, 170.7, 170.5, 145.8, 100.2,
steps) using general procedures 4 and 5A. (42%) after 2-steps 74.9, 69.7, 66.9, 66.5, 62.5, 21.2, 20.9 (2); TOF HRMS (DART)
using general procedures 4 and 5B. (44%) after 2-steps using m/z calcd for C15H24O9N (M+NH4)+ 362.1451, found 362.1455.
general procedures-4 and 5C. (31%) after 2-steps using general
procedures-4 and 5D. (64%) after 2-steps using general Compound 33. Obtained as colorless oil in 55% yield from 23
procedures-4 and 5E. Rf 0.45 (1:1 Hex:EtOAc); [α]D +73.1 (c 1.5, after two steps using the general procedures-4 and 5A. Rf 0.5
1
CHCl3); 1HNMR (400 MHz, CDCl3) δ 6.49 (d, J = 6.9 Hz, 1H), (5:2 Hex:EtOAc); [α]D -263.9 (c 0.7, CHCl3); HNMR (400 MHz,
5.39-5.36 (dd, J = 5.9 Hz, 1H), 5.24-5.18 (m, 2H), 4.85-4.81 (dd, CDCl3) δ 8.03-7.97 (m, 8H), 7.53-7.50 (m, 4H), 7.41-7.34 (m,
J = 6.9 Hz, 1H), 4.58 - 4.55 (m, 1H), 4.34-4.30 (dd, J = 12.2, 5.1 8H), 6.65-6.63 (d, J = 6.8 Hz, 1H), 6.24 (m, 1H), 5.82 (m, 2H),
Hz, 1H), 4.20-4.17 (dd, J = 12.2, 1.8 Hz, 1H), 2.17 (s, 6H), 2.09 5.02-5.00 (dd, J = 6.6, 3.6 Hz, 1H), 4.66-4.54 (m, 3H); 13CNMR
(s, 3H), 2.07 (s, 3H); 13CNMR (100 MHz, CDCl3) δ 169.8, 169.6, (100 MHz, CDCl3) δ 166.3, 165.8, 165.4, 164.9, 149.0, 133.8,
169.0, 150.3, 103.1, 79.0, 73.8, 71.5, 67.5, 63.4, 21.2, 21.0, 133.5, 133.3, 130.1, 130.0, 129.9, 129.7, 129.6, 129.0, 128.7,
20.9; TOF HRMS (DART) m/z calcd for C15H24O9N (M+NH4)+ 128.6, 128.5,106.4, 81.0, 74.1, 71.0, 69.5, 63.9; TOF HRMS
362.1451, found 362.1458.
(DART) m/z calcd for C35H32O9 (M+H)+ 610.2077, found
610.2068.
Compound 14. Obtained as colorless oil in 35% yield from 13
after two steps using general procedures 4 and 5A. Rf 0.45 (5:2 Compound 35. To a solution of 34 (0.10 g, 0.21 mmol, 1 eq.) in
Hex:EtOAc); [α]D -111.8 (c 0.6, CHCl3); 1HNMR (400 MHz, CDCl3) DCM (1 mL) was added TMSBr (0.27 mL, 2.1 mmol, 1 eq.) at 0
δ 6.50-6.47 (dd, J = 6.3, 1.6 Hz, 1H), 5.58-5.56 (m, 1H), 5.47- °C. The mixture was allowed to warm to rt and then stirred for
5.56 (m, 1H), 4.76-4.73 (ddd, J = 6.3, 2.6, 1.4 Hz, 1H), 4.36-4.21 ~24 h. After, the solvent was removed under reduced pressure
(m, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 2.04 (s, 3H); 13CNMR (100 and followed by reductive elimination general procedure 5E
MHz, CDCl3) δ 170.7, 170.5, 170.3, 145.6, 99.0, 73.0, 64.1, 63.9, provided 35 in 20% yield as
a tan/off-white powder.
62.1, 21.0, 20.9, 20.8; TOF HRMS (DART) m/z calcd for Characterization data for 35 coincided with that of the
C12H20O7N (M+NH4)+ 290.1240, found 290.1238.
material previously reported by us.
Compound 19. Obtained as colorless oil in 48% yield from 18
Notes and references
after two steps using general procedures-4 and 5A. Rf 0.45 (5:2
1
Hex:EtOAc); [α]D -33.8 (c 2, CHCl3); HNMR (400 MHz, CDCl3) δ
1
The triply unsaturated seven membered oxacycle is formally
an oxepine. We and others have also referred to the tetra-
hydro variants as oxepines. See references 2 and 5.
N. L. Snyder, H. M. Haines and M. W. Peczuh, Tetrahedron,
2006, 62, 9301.
(a) S. J. Danishefsky and M. T. Bilodeau, Angew. Chem., Int.
Ed. Engl., 1996, 35, 1380. (b) P. H. Seeberger, M.T. Bilodeau
and S.J. Danishefsky Aldrichim. Acta 1997, 30, 75. (c) R. L.
6.41-6.38 (dd, J = 6.8, 1.5 Hz, 1H), 5.77-5.75 (m, 1H), 5.23-5.22
( m, 1H ), 5.12-5.09 ( dd, J = 8.9, 4.1 Hz, 1H), 4.67-4.64 (ddd, J =
6.8, 3.4, 1.0 Hz, 1H), 4.27-4.23 (dd, J = 11.7, 5.9 Hz, 1H), 4.19-
4.10 (m, 2H), 2.06-2.05 (m, 9H), 2.02 (s, 3 H); 13CNMR (100
MHz, CDCl3) δ 170.7, 170.3, 169.8, 169.1, 148.4, 105.4, 80.5,
73.3, 70.4, 68.4, 63.2, 21.1, 21.0, 20.9; TOF HRMS (DART) m/z
calcd for C15H24O9N (M+NH4)+ 362.1451, found 362.1456.
2
3
Halcomb and S. J. Danishefsky, J. Am. Chem. Soc., 1989, 111
,
6661. (d) D. Horton, W. Priebe, and M. Sznaidman
Carbohydr. Res. 1990, 205, 71. (e) Honda, E. and D. Y. Gin, J.
Am. Chem. Soc., 2002, 124, 7343. (f) F. W. Lichtenthaler,
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(a) L. V. Reddy, V. Kumar, R. Sagar and A. K. Shaw, Chem Rev,
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Tetrahedron Lett., 2010, 51, 6259. (c) G. Pazos, M. Pérez, Z.
Compounds 25 and 26. Obtained as colorless oil with 1:1
mixture of isomers after two steps as follows: (55%) using the
general procedures 4 and 5A; (46%) using the general
procedures 4 and 5C; (52%) using the general procedures 4
and 5D.
4
Gándara, G. Gómez and Y. Fall, Org. Biomol. Chem., 2014, 12
7750. (d) P. Saidhareddy and A.K. Shaw, RSC Advances, 2015,
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125, 8798.
,
Compound 25. Rf 0.4 (5:2 Hex:EtOAc); [α]D -71.7 (c 0.5, CHCl3);
1HNMR (400 MHz, CDCl3) δ 6.36-6.34 (dd, J = 7.7, 2.3 Hz, 1H),
5.73- 5.70 (ddd, J = 2.7, 2.7, 9.2 Hz, 1H), 5.49 (d, J = 2.7 Hz, 1H),
5.09-5.07 (dd, J = 9.3, 2.7 Hz, 1H), 4.70-4.68 (dd, J = 7.6, 3.1 Hz,
1H), 4.19- 4.15 (m, 2H), 4.07-4.03 (m, 1H), 2.16 (s, 3H), 2.08 (s,
3H), 2.07 (s, 3H), 2.03 (s, 3H); 13CNMR (100 MHz, CDCl3) δ
170.6, 170.3, 170.2, 170.0, 145.9, 106.9, 76.8, 73.1, 68.5, 68.4,
5
5
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5
6
(a) J. Saha and M. W. Peczuh, Adv. Carbohydr. Chem. 25 S.H Boyer, B.G. Ugarkar and M.D. Erion, Tetrahedron
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26 In fact, when tetra-O-benzyl analog
9 was exposed to HBr in
(a) M. R. Duff, W. S. Fyvie, S. D. Markad, A. E. Frankel, C. V.
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AcOH, an unexpected, intramolecular cyclization product
arose rather than the expected anomeric bromide. Details of
this reactivity will be reported separately.
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29 C. L. Forbes and R. W. Franck J. Org. Chem., 1999, 64, 1424.
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23 See Supplementary Information for additional details.
24 Unsuccessful hydrogenation conditions included 20%
Pd(OH)2 in 2:1 CH3OH:CHCl3 and 10% Pd/C in EtOAc.
8 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6OB00262E
A practical and scalable synthesis of carbohydrate based oxepines
Raghu Vannam and Mark W. Peczuh
a "new-old" approach to oxepines
OAc
O
O
O
BnO
AcO
AcO
OH
OAc
practical • simple • scalable
A versatile synthetic route that converts pyranoses to oxepines via reductive elimination of septanosyl
bromides is reported.