A Migratory Ether Formation Route to Medium-Sized Sugar Mimetics

Article abstract of DOI:10.1002/anie.201608974

Polyol-substituted cyclic ethers are fundamental building blocks of biomolecules. The position and stereochemistry of multiple hydroxy substituents of cyclic ethers play a central role in their biological function. Current methods for the synthesis of such structures are limited to “naked” ring products with no or few substituents. Here we describe a general route to medium-sized polyol cyclic ethers using a migratory ether formation strategy. In contrast to the common pathway of direct opening of epoxides, Me₃Al was found to promote an unprecedented ether addition reaction, opening a neighboring epoxide. The resulting oxonium intermediate triggers a 1,3-methyl shift to yield 2-deoxyribital products. When the hemiacetal auxiliary is a monosaccharide, the sugar ring is expanded by four atoms to give the corresponding 9- to 11-membered analogues. This method provides an entry into the untapped chemical space of medium-sized sugar mimetics.

Full text of DOI:10.1002/anie.201608974

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201608974
German Edition: DOI: 10.1002/ange.201608974
Medium-Sized Rings
A Migratory Ether Formation Route to Medium-Sized Sugar Mimetics
Hao Jiang, Li-Ping Xu, Yan Fang, Zhen-Xing Zhang, Zhen Yang,* and Yong Huang*
Abstract: Polyol-substituted cyclic ethers are fundamental
building blocks of biomolecules. The position and stereochem-
istry of multiple hydroxy substituents of cyclic ethers play
a central role in their biological function. Current methods for
the synthesis of such structures are limited to “naked” ring
products with no or few substituents. Here we describe a general
route to medium-sized polyol cyclic ethers using a migratory
ether formation strategy. In contrast to the common pathway of
direct opening of epoxides, Me Al was found to promote an
3
unprecedented ether addition reaction, opening a neighboring
epoxide. The resulting oxonium intermediate triggers a 1,3-
methyl shift to yield 2-deoxyribital products. When the hemi-
acetal auxiliary is a monosaccharide, the sugar ring is
expanded by four atoms to give the corresponding 9- to 11-
membered analogues. This method provides an entry into the
untapped chemical space of medium-sized sugar mimetics.
P
olyol-substituted cyclic ethers are fundamental structural
motifs for biomolecules, natural products and pharmaceutical
[
1]
agents. Five- and six-membered polyol cyclic ethers, pen-
Scheme 1. Polyol cyclic ethers.
toses and hexoses for example, are basic building blocks of the
[
2]
backbones of DNA, RNA and glycans (Scheme 1a). The
structural and functional diversity of these biomolecules
originates from their numerous isomers with differently
[
7]
expansion (Scheme 1b), but the applicability of these
methods quickly diminishes as the number of substituents,
especially hydroxy groups, increases. These OH groups
complicate the critical ring closure process by creating extra
bond opposition forces (Pitzer strain) and unintended hydro-
gen bonds. So far, no synthesis is available for medium-sized
polyol cyclic ethers, a class of molecules that might possess
sugar-like properties. Here, we report a migratory ether
formation strategy to synthesize 9- to 11-membered cyclic
ethers (Scheme 1c). This unprecedented transformation fea-
tures a relay ring-opening process that expands the ring size of
the starting material by 4 atoms. In view of the readily
accessible 5-, 6-, and 7-membered cyclic ethers, this protocol is
particularly attractive for the construction of 9- to 11-
membered medium-sized rings. Importantly, this method
allows convenient stereospecific introduction of multiple
hydroxy substituents using starting materials derived from
sugars.
[3]
substituted hydroxy groups. As a consequence, considerable
effort has been devoted to the synthesis of polyol cyclic
[4]
ethers. Many syntheses of five- and six-membered mono-
saccharides have been reported but synthetic and biological
[
5]
studies of larger ring analogues are very few. In general, 7-
to 11-membered cyclic scaffolds, often referred to as medium-
sized rings, are the most difficult of all ring systems to
construct. Kinetically, large entropic penalties significantly
reduce the probability of the appropriate cyclization reaction.
Thermodynamically, transannular orbital interactions in
medium-sized rings create extra ring strain in both the
transition states and the products. Among medium sized
cyclic systems, 9- to 11-membered rings are most challenging
from a synthetic point of view. There are two general
[
4,6]
approaches to this problem: macrocyclization
and ring
This novel transformation (Scheme 1c) emerged from our
[
*] Dr. H. Jiang, Dr. L.-P. Xu, Dr. Y. Fang, Dr. Z.-X. Zhang,
Prof. Dr. Z. Yang, Prof. Dr. Y. Huang
Key Laboratory of Chemical Genomics
Peking University Shenzhen Graduate School
Shenzhen, 518055 (China)
[8]
investigation of a nucleophilic epoxide-opening reaction.
Epoxy methanols, readily available in optically enriched
[
9]
forms via the Sharpless epoxidation reaction, are popular
synthons for a number of highly sought-after chiral scaf-
E-mail: zyang@pku.edu.cn
[10]
folds. Epoxy alcohols are particularly susceptible to various
huangyong@pkusz.edu.cn
nucleophilic addition reactions in the presence of a Lewis
Dr. L.-P. Xu
[
11]
acid. With tight chelation control, these reactions generally
occur with exclusive regio- and stereochemical control. Ring-
opening of epoxy alcohols using an alkylaluminum reagent
for example, is a classical method for the preparation of useful
School of Chemical Engineering, Shandong University of Technology
Zibo, 255049 (P. R. China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
[12]
1002/anie.201608974.
chiral diols with an adjacent carbon stereogenic center.
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When we treated Me Al with a substrate (1) bearing a p-
reaction. A density functional theory (DFT) study was
3
methoxybenzyloxy (PMBO) group two carbons away, the
conducted for the reaction using epoxymethanol (2a) and
expected 3-methylpentanediol derivative 1b was obtained in
high yield as the sole product (Scheme 2a). In contrast, we
Me Al (Scheme 4). Substrate 2a has two stable conforma-
tions and the folded, chair-like conformer is 3.0 kcalmol
3
[
13]
À1
more stable than the linear conformer. Upon mixing Me Al
3
Scheme 2. Ring-opening reactions of 2,3-epoxy alcohols using trime-
thylaluminum.
found that the epoxide-opening pathway was completely
avoided when the PMBO group was replaced by benzyloxy-
methoxy (BOMO) group. Instead of opening the epoxide
directly, Me Al attacked the hemiacetal carbon, causing the
3
benzyloxy residue to open the epoxide. As a result, the
protected 2-deoxyribital (3a) was isolated in 83% yield
(
Scheme 2b).
Migration of the alkoxy group could be either intra- or
intermolecular. For intramolecular transfer, epoxide-opening
would occur either before the attack of Me Al or in concert
3
with it. In the intermolecular pathway, Me Al would react
3
well before the opening of the epoxide. In order to distinguish
these two possibilities, a cross-over experiment was carried
out. A pair of substrates with different hemiacetal groups was
subjected together to reaction with Me Al. In order to
3
distinguish the intra- and intermolecular products, extra
methyl groups were introduced to one substrate. High
resolution mass spectrometry (HRMS) clearly showed the
existence of only the intramolecular products (Scheme 3).
Scheme 4. Energy profiles and optimized structures for complex for-
mation, epoxide-opening and methylation steps.
with 2a, gas bubbles were immediately observed and the
reaction became highly exothermic. Calculations suggested
two molecules of Me Al bound to the epoxy alcohol oxygens,
3
releasing one molecule of methane. The third Me Al coor-
3
dinates to either O3 or O4 of the hemiacetal. Computer
minimization yielded two distinct complex conformers 2a-I
(O3-bonded) and 2a-II (O4-bonded), which adopt chair and
linear conformations, respectively. Due to the electrostatic
attraction between O4 and C3, 2a-I is more stable than 2a-II
by 5.5 kcalmol . This interaction facilitates epoxide opening
Scheme 3. Crossover experiments.
À1
by O4 to generate the oxonium intermediate 2a-III, in which
The reaction is sensitive to the amount of Me Al used.
the hemiacetal carbon C6 is exposed to the O3-bound Me Al.
3
3
The reaction employing 1.0 equivalent of Me Al led to
Subsequent 1,3-methyl migration gives the desired product
3
a complex mixture with very little 2-deoxyribital product. In
3a. Based on the minimized structure of 2a-III, the O2-bound
the presence of 2.0 equivalents of Me Al, the product (3a)
Me Al is too distant to react with either C6 or the benzylic
3
3
was isolated in 22% yield. Complete conversion was achieved
with 3.0 equivalents of the aluminum reagent. These data
carbon.
In addition to Me Al, Et Al and Et Zn were also tested in
3
3
2
suggest that three Me Al molecules are involved in this
this migratory ether formation reaction. Comparable yields
3
2
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were obtained for higher order alkylaluminum reagents but
cyclic hemiacetal contains a racemic stereogenic center. The
Et Zn alone failed to react with substrate 2a. However,
reaction could be conveniently scaled up to 75 mmol without
compromising the yields.
2
addition of 3.0 equivalents of ZnCl or trifluoroacetic acid led
2
to smooth conversion to the desired 2-deoxyribitol products.
Various 2,3-epoxy pentanol analogues were prepared and
examined (Figure 1). The reaction conditions showed gener-
We next examined whether the terminal alcohol is
[14]
required for the reaction. Schneider and Brauner reported
that a normal ring opening reaction occurs for simple terminal
[
15]
epoxides with Me Al (Scheme 5a).
We found that the
3
migratory ether formation proceeds smoothly for a substrate
Scheme 5. Results and calculations for substrates lacking a terminal
hydroxy group.
Figure 1. AlMe -mediated migratory epoxide-opening reaction. The
3
reactions were carried out at room temperature for 24 h, except for
products 3c and 3 f. Complete conversions to these two products were
accomplished in 4–6 h.
bearing a methoxymethoxy (MOMO) group (Scheme 5b).
Interestingly, when the hemiacetal was replaced by a benzyl-
oxymethoxy (BOMO) group, the expected benzyloxy migra-
tion failed to occur. Instead, the reaction proceeded with
debenzylation to give a 1,3-dioxanylmethanol product (3k),
which was isolated in high yield (Scheme 5c). Energy profiles
were mapped for the formation of 3j and 3k. In the absence
of the free hydroxy functionality, the oxonium intermediate
(2j-IV) has two decomposition pathways: 2j-TS1 and 2j-TS2.
For the MOMO substrate (2j), the four-membered migratory
ality towards hemiacetal, trialkylaluminum and substituents
at C4 and C5. Good yields were uniformly observed after
2
4 h. Interestingly, gem-dialkyl substituted substrates reacted
noticeably more rapidly. The reactions reached completion
after 4 to 6 h, the beneficial Thorpe–Ingold effect of these
substituents apparently overriding the steric hindrance. When
a phenol-derived hemiacetal was used, the phenoxy group
migrated with similar efficiency despite its reduced nucleo-
philicity. Encouraged by these results, we examined cyclic
hemiacetal analogues and found that 5-, 6-, and 7-membered
cyclic hemiacetals all participate in this migratory ring
expansion reaction leading, respectively to 9-, 10, and 11-
membered cyclic ethers which were formed with good yields.
Due to lack of communication between the epoxyalcohol and
hemiacetal functionalities, no steric bias was observed when
À1
transition state 2j-TS2 is more stable by 15.9 kcalmol
(Scheme 5d) but in sharp contrast, the six-membered deben-
zylation pathway through 2k-TS1 leading to 3k and ethyl-
benzene as a by-product (Scheme 5e) is more favorable by
À1
13.5 kcalmol .
In order to access polyol-substituted medium-sized cyclic
ethers, we examined sugar-substituted epoxy alcohol sub-
[
16]
strates.
Despite multiple oxygen atoms on the sugar
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absolute stereochemistry for C7–C10 is determined by the
type of sugar used and the stereochemistry at C2 and C3 is
determined by the configuration of the epoxide. The relative
stereochemistry for product 3p was confirmed by X-ray
[
17]
crystallography. Both d- and l-sugars reacted with similar
efficiency, suggesting little steric interference from the chiral
epoxide. Both pyranoses and furanoses are compatible,
leading to 9- and 10-membered cyclic products. To date,
there are no alternative synthetic methods for these medium-
sized sugar mimetics.
In conclusion, we have discovered a novel, trialkylalumi-
num-mediated, migratory ether formation reaction using
epoxyalcohols bearing a hemiacetal terminal. Instead of
directly opening the epoxide, the Lewis acid aluminum
reagent promotes an intramolecular oxy-addition to the
epoxide, and this triggers a migratory alkylation reaction. 2-
Deoxyribitals can be prepared in good yield by this reaction.
Computational studies suggest that a chair-like conformation
of a trialuminum bonded complex is responsible for the facile
addition of the ether to the epoxide. Significantly, reactions
using sugar-tagged substrates lead to the first general syn-
thesis of a family of novel medium-sized sugar mimetics. We
expect these new chemical syntheses will find wide applica-
tions in glycan chemistry and medicinal chemistry.
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (21372013, 21572004 for Y.H.),
the Guangdong Province Special Branch Program
(
2014TX01R111), the Guangdong Natural Science Founda-
tion (2014A030312004), and the Shenzhen municipality
KQTD201103, JCYJ20160226105602871,
JSGG20140717102922014).
(
Keywords: medium-sized rings · migratory ether formation ·
ring-opening reactions · sugar · trimethyl alumininum
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Communications
Medium-Sized Rings
H. Jiang, L.-P. Xu, Y. Fang, Z.-X. Zhang,
Z. Yang,* Y. Huang*
&&&& — &&&&
A Migratory Ether Formation Route to
Medium-Sized Sugar Mimetics
Biomolecular building blocks: In a gen-
eral route to medium-sized polyol cyclic
methyl shift to yield 2-deoxyribital prod-
ucts. When the hemiacetal auxiliary is
a monosaccharide, the sugar ring is
expanded by four atoms to give the 9- to
11-membered analogues.
ethers, Me Al promotes an unprece-
3
dented intramolecular epoxide-opening
by an ether addition reaction. The result-
ing oxonium intermediate triggers a 1,3-
6
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