Synthesis of C-septanosides from pyranoses via vinyl addition and electrophilic cyclization

Article abstract of DOI:10.1021/ol401769k

A two-step synthesis of C-septanosides from pyranoses is reported. Vinyl addition to tetra-O-benzyl d-glucose, d-galactose, and d-mannose gave the corresponding allylic alcohols. Electrophilic cyclization followed by treatment with iodine gave iodomethyl C-septanosides suitable for substitution reactions. The cyclizations were diastereoselective, giving cis-1,2 configured C-septanosides. Selectivity is rationalized through a model for electrophilic additions that invokes the conformation of the allylic system. This new approach should be generally applicable to the synthesis of a variety of C-septanosides.

Full text of DOI:10.1021/ol401769k

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Synthesis of C‑Septanosides from
Pyranoses via Vinyl Addition and
Electrophilic Cyclization
Raghu Vannam and Mark W. Peczuh*
Department of Chemistry, University of Connecticut, 55 North Eagleville Road, U-3060,
Storrs, Connecticut 06269, United States
mark.peczuh@uconn.edu
Received June 22, 2013
ABSTRACT
A two-step synthesis of C-septanosides from pyranoses is reported. Vinyl addition to tetra-O-benzyl D-glucose, D-galactose, and D-mannose gave the
corresponding allylic alcohols. Electrophilic cyclization followed by treatment with iodine gave iodomethyl C-septanosides suitable for substitution reactions.
The cyclizations were diastereoselective, giving cis-1,2 configured C-septanosides. Selectivity is rationalized through a model for electrophilic additions that
invokes the conformation of the allylic system. This new approach should be generally applicable to the synthesis of a variety of C-septanosides.
Compounds containing a seven-membered ring such as
polyhydroxylated azepanes and septanose carbohydrates
have received considerable attention over the past decade
as potential “non-natural” surrogates for pyranoses in a
number of biochemical settings.1 In one example, a poly-
hydroxylated azepane designed to mimic the stereo-
chemistry and functional groups of N-acetyl glucosamine
inhibited a human O-GlcNAcase.2 A number of other
reports have detailed the inhibition of glycosidases using
azepanes and related compounds.3 With respect to septa-
nosides, we have demonstrated that methyl β-septanosides
can bind competitively into the pyranose binding pocket of
Concanavalin A, a plant lectin that normally recognizes
R-mannosides.4 Nitrophenyl septanosides have been used
as substrates of naturally occurring R- and β-glycosidases,
but the kcat and KM values suggested that they were
relatively poor substrates.5 It may be that septanosides
will be poor substrates for glycosidases in general and
therefore able to evade degradation in cellular contexts.
Under acidic conditions, however, we have observed that
hydrolysis of septanosides is more facile than for pyrano-
sides.6 This presumably owes to the lower stability of seven-
membered rings in comparison to six-membered rings.7 If
septanosides are more susceptible to acid hydrolysis, then,
access to C-glycosides will be important to their application
in biological contexts. C-Glycosides are analogs of pyra-
noses that take up conformations that are very similar to the
corresponding sugars and have similar protein-binding
profiles.8 By design, they are also resistant to both enzymatic
and acidic hydrolysis by virtue of the fact that the glycosidic
CꢀO linkage has been replaced with a CꢀC bond.9
To that end, we anticipated that C-septanosides could
be prepared via electrophilic cyclization of the appropriate
enitols. The approach has been used to synthesize
C-pyranosides; in this case, the sequence involves
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r
10.1021/ol401769k
XXXX American Chemical Society

corresponding iodomethyl compound. This, in turn, could
be used as an electrophile for the preparation of a variety
of C-septanoside conjugates.
Scheme 1. Synthesis of C-Septanoside 4 via Vinylation and
Electrophilic Cyclization
Our implementation of the strategy is illustrated using
tetra-O-benzyl-D-glucose 1 in Scheme 1. Addition of vinyl
magnesium bromide to 1 gave a 3:2 mixture of diastereo-
meric allylic alcohols (78% combined yield). In our hands,
the yield and selectivity of the addition were slightly lower
than has been reported;12,14 the procedure was sufficient
enough, however, to obtain material for the subsequent
reactions without optimization. The major isomer, 2, was
treated with Hg(OTFA)2 in THF followed by I2 in DCM.
The product of the two-step process, to our delight, was
iodomethyl compound 3 which was obtained in 53% yield
over the two steps. At this stage, the stereochemistry of the
newly created stereocenter at C2 (glycosidic numbering)
was uncertain. To facilitate characterization of the stereo-
chemistry of the new compound, we chose to dehalogenate
the iodomethyl group and also to convert the benzyl
protecting groups to acetates via hydrogenation and acetyla-
tion, which gave C-septanoside 4 in 92% yield. The 13C and,
importantly, 1H NMR spectra for 4 were simpler to interpret
in comparison to 3. Diagnostic cross-peaks in the NOESY
spectrum of 4 (CDCl3) between H1ꢀH2, H1ꢀH4, and
H1ꢀH6 were considered diagnostic for the cis-1,2 “β” config-
3
uration shown in Scheme 1. Additionally, the low JH1,H2
coupling (3.3 Hz) constant also supported the cis configura-
tion of protons at the C1 and C2 positions. The minor isomer
of vinyl addition to glucose, which is epimeric at the allylic
alcohol carbon relative to 2, was subjected to the same reaction
sequence; analysis of NMR spectra of the product, as had
been done for characterization of 4 previously, led to assign-
ment of cis-1,2 C-septanoside 5 as the structure (Figure 1).15
Through the same set of reactions, tetra-O-benzyl-D-galactose
was converted to 6 and 7, respectively.12,16 Moreover, our
structural assignment of 4ꢀ7was fortified by the inside alkoxy
model for that rationalizes stereoselectivity for additions to
chiral allylic systems.17,18
Figure 1. Products (4ꢀ7) of vinylationꢀcyclization sequence in
the D-gluco and D-galacto series.
generation of the enitol by Wittig olefination of a pyranose10
or vinyl addition to a pentose followed by Hg2þ cycliza-
tion.11 This strategy was originally utilized to stereoselec-
tively prepare R-D-C-glucopyranose derivatives and later
other, rarer C-glycosyl compounds. Since then, it has been
used to prepare numerous biologically active C-glycosyl
derivatives.12 The key question to us (Scheme 1) was
whether the cyclization of species such as 2 to form a
seven-membered ring would be favored over other reac-
tions (e.g., intermolecular etherification, intramolecular
attack of a benzyl ether, etc.). There is ample literature
precedent for the addition of vinyl Grignards to aldo-
hexoses.13 Cyclization using Hg2þ as an electrophile would
give analkyl mercury species that could be convertedtothe
Stereoselectivity in the cyclization reaction is linked to
the absolute configuration at the allylic carbon. The π-bond
is nucleophilic when it is coplanar with the CꢀO bond of
the allylic carbon (e.g., I or II) because, in this conforma-
tion, its electron density is localized on the π-bond itself
rather than delocalized into the σ* of the CꢀO bond.16,17
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(15) Cyclization products en route to and including 5 have ∼10%
inseparable impurity which we have tentatively been assigned as the 1,2-
trans product. More details are in the Supporting Information.
(16) The Supporting Information contains details on the synthesis of
compounds 5ꢀ7.
(17) Chamberlin, A. R.; Mulholland, R. L.; Kahn, S. D.; Hehre, W. J.
J. Am. Chem. Soc. 1987, 109, 672–677.
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Scheme 2. Reactions Utilizing the Iodomethyl Group of C-Septanoside 3
From here, attack on the electrophile occurs syn to the allylic
hydrogen to give a π-complex. Hehre et al. have commented
that, for intramolecular reactions, attack is on the Hg2þ
olefin π-complex and not onto the onium ion itself. Attack
on this complex by the pendant hydroxyl group leads to
the cyclized product. Our structural assignment of cis-1,2
C-septanosides 4ꢀ7, based on NMR spectra, corresponds
with the inside alkoxy model. The model has been used to
rationalize several related cyclization reactions.11b,19
An attractive feature of the synthesis is that its product
contains an alkyl iodide that can be enlisted for subsequent
reactions. Scheme 2 collects a number of examples using
the reactive alkyl iodide unit of C-septanoside 3. Substitu-
tion by nucleophiles such as octane thiol, thioacetate, and
azide produced compounds 8ꢀ10 in 82%, 95%, and 76%
yields, respectively.20 A mild procedure for conversion of
alkyl iodides to alcohols21 was used to convert 3 to diol 11
in 62% yield over three steps. The C2 hydroxyl group was
protected as the acetate in this sequence to avoid formation
of the oxetane in the hydroxylation reaction. Overall,
oxetane formation was relatively facile as in the conversion
of 3 to 12 in the presence of DBU (93%). Arbuzov reactions
under two different circumstances were also explored.
Protection of the C2 hydroxyl group as the TBS ether
followed by phosphonate formation gave 13 (65% yield
over two steps).21 Alternatively, if the C2 hydroxyl group
was left unprotected, attack by triethyl phosphite gave cyclic
phosphonate 14 in 80% yield as a mixture of diastereomers
that are epimeric at the phosphorus atom.22 Finally, oxida-
tion of the C2 hydroxyl group using PCC provided ketone
15 in 92% yield.23 Interestingly, elimination of HI from 15
to give the conjugated enone was unsuccessful when using
either collidine or DBU as a base (vide infra).
A more complex distribution of products was obtained
when tetra-O-benzyl mannose was the starting material for
the synthesis (Scheme 3). Addition of vinyl magnesium
bromide to tetra-O-benzyl-mannose resulted in an insepara-
ble mixture (3:2) of diastereomeric allylic alcohols 16
(72%). The mixture was put under the cyclization reaction
conditions with the expectation that, based on the results
of the previous substrates, each of the allylic alcohols
would give its corresponding C-septanoside. Instead, the
reaction ended up giving three different products, only one
of which was a C-septanoside.
The major product of the cyclization, 17, was isolated in
43% yield and followed a reaction course similar to the
other septanosides. The other two products arose from
different pathways, however. It was apparent from the 1H
NMR spectra of 18 and 19 that a benzyl group had been
lost from these compounds over the course of the reaction.
This observation suggested they cyclized via a nucleophilic
benzyl ether oxygen, which has several precedents.12,24,25
As was done previously, the assignment of structures
17ꢀ19 was made by inference from a collection of NMR
spectra of the corresponding acetyl protected compounds
20ꢀ22. The key spectral data used to assign a structure
for 20 were NOESY crosspeaks between H1ꢀH2 and
1
H1ꢀH5. Analysis of H, COSY, NOESY, HSQC, and
HMBC spectra for 21 (CDCl3) provided compelling evi-
dence for its structure. A NOESY correlation between
H1ꢀH4 was one key data point as well as HMBC correla-
tions for acetyl carbonyls to C2, C3, and C5ꢀC7 but not to
C4. Formation of the five-membered ring using a benzyl
ether oxygen as a nucleophile has been utilized extensively
in the formation of highly substituted tetrahydrofurans.
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M. L.; Taylor, R. J. K. Eur. J. Org. Chem. 2002, 1323–1336. (b)
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2004, 12, 5495–5503.
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G. J. Org. Chem. 1996, 61, 3428–3432.
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Peczuh, M. W. J. Org. Chem. 2008, 73, 6341–6354. (c) Cipolla, L.; Lay,
L.; Nicotra, F. J. Org. Chem. 1997, 62, 6678–6681.
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Org. Lett., Vol. XX, No. XX, XXXX
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Scheme 3. Cyclization Products of Allylic Alcohol 16
Scheme 4. Reactions of the R-C-Septanosides
cycloaddition product 27 in 70% yield. We noted that 25
decomposed over time but it also could be intercepted if
used soon after its preparation. We trapped it via a Huisgen
addition reaction to form dihydropyrazole 26 (62%) as
shown Scheme 4.28 This result suggests that enone 25 and
related compounds may be starting materials for a variety of
additional reactions and underscores their potential for ap-
plication as C-glycoside analogs of septanose carbohydrates.
The method for the diastereoselective synthesis of
C-septanosides described here benefits from its utilization
of readily available starting materials and the ability to
create a variety of derivatives from the cyclization products.
We have demonstrated the route using benzyl protected
D-glucose, D-galactose, and D-mannose, but the route is
likely amenable to a greater number of pyranoses; this is
important because we and others have observed that, in the
appropriate contexts, septanoses can be used as surrogates
for pyranose sugars. Also, the new C-septanosides should be
significantly more stable toward hydrolysis in comparison
to O-septanosides. Attack by nucleophiles on the iodo-
methyl group that arises via the cyclization provided a
variety of functionalized C-septanosides (e.g., 10ꢀ14). The
cyclization products can also undergo other reactions such
as dimerization or addition reactions of enones such as 25.
Our current efforts are aimed at utilizing the new addition
and cyclization method for the synthesis of C-septanoside
analogs to be tested for their ability to bind target proteins.
The inherent nucleophilicity of the ether oxygen and the
favorable kinetics for the formation of five-membered
rings are consistent with this assignment. HMBC data
for 22 also showed that the C4 hydroxy group was not
acetylated which prompted us to assign the structure as a
substituted tetrahydrofuran. The spectra for 22 were dis-
tinct from those of 21 but nonetheless similar. Based on
these observations we have tentatively assigned the last
cyclization product as the trans-1,2 isomer 22.
We have also observed some interesting differences in
the outcomes of reactions of R- and β-C-septanosides. In
the glucose series, for example, treatment of β-C-septano-
side 3 with DBU in THF gave oxetane 12 (Scheme 2).
Treatment of the R-diastereomer 23, on the other hand,
gave exoglycal 24 in 66% yield (Scheme 4). One argu-
ment26 to rationalize these observations is based on the
ability of the C2 hydroxyl to form a H-bond with the C3
benzyloxy group in 23 but not in 3. Maintenance of the
H-bond may make it difficult to deprotonate and thereby
favor the elimination reaction to form 24. Oxidation of the
C2 hydroxyl of 3 gave ketone 15, but when the subsequent
elimination of HI across the C1-iodomethyl bond was
attempted no reaction occurred. In contrast, PCC oxida-
tion and collidine elimination of 23 gave enone 25 in 52%
yield over two steps (Scheme 4). Successful elimination
based on the opposite stereochemistry at C1 was consistent
with different outcomes in DBU elimination of 3 and 23.
Formation of enone 25 was unexpected because previous
work had shown that such compounds usually undergo
facile cycloaddition reactions. Specifically, we and others
have reported homodimerizations or in situ trapping of
these enones with dienophiles.22,27 Oxidation and elimina-
tion starting from 17, for example, provided dimeric
Acknowledgment. This work was partially supported
by a CAREER award (CHE-0546311) to M.W.P. from the
NSF. 400 MHz/100 MHz NMR spectra were collected on
an instrument that was upgraded by an NSF-CRIF grant
(CHE-0947019).
Supporting Information Available. Additional data,
experimental procedures, and characterization data for
all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(26) A figure and comments on the difference in reactivity of 3 and 23
are in the Supporting Information.
(27) (a) Saha, J.; Lorenc, C.; Surana, B.; Peczuh, M. W. J. Org. Chem.
2012, 77, 3846–3858. (b) Ireland, R. E.; Daub, J. P. J. Org. Chem. 1983,
48, 1303–1312.
(28) Nair, V.; Mathew, S. C.; Biju, A. T.; Suresh, E. Angew. Chem.,
Int. Ed. 2007, 46, 2070–2073.
The authors declare no competing financial interest.
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