Abstract A new class of nitrogen-containing endoperoxides were synthesised by a photochemical [4 + 2]-cycloaddition between a diene and singlet oxygen. The endoperoxides were dihydroxylated and protected to provide a series of endoperoxide building blocks for organic synthesis, with potential use as precursors for the synthesis of branched azasugars. Preliminary exploration of the chemistry of these building blocks provided access to a variety of derivatives including tetrahydrofurans, epoxides and protected aminotetraols. 64

Daniel Sejer Pedersen

Henrik Johansson

Mark Bjerregaard

Svenja Domeyer

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Exploring endoperoxides as a new entry for the synthesis of
branched azasugars
Svenja Domeyer, Mark Bjerregaard, Henrik Johansson and Daniel Sejer Pedersen*
Full Research Paper Open Access
Address:
Department of Drug Design and Pharmacology, University of
Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark
Email:
Daniel Sejer Pedersen* - daniel.pedersen@sund.ku.dk
* Corresponding author
Keywords:
azasugar; carbohydrate; cycloaddition; endoperoxide; photochemistry
Beilstein J. Org. Chem. 2017, 13, 644–647.
doi:10.3762/bjoc.13.63
Received: 16 December 2016
Accepted: 13 March 2017
Published: 03 April 2017
Associate Editor: S. Flitsch
© 2017 Domeyer et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A new class of nitrogen-containing endoperoxides were synthesised by a photochemical [4 + 2]-cycloaddition between a diene and
singlet oxygen. The endoperoxides were dihydroxylated and protected to provide a series of endoperoxide building blocks for
organic synthesis, with potential use as precursors for the synthesis of branched azasugars. Preliminary exploration of the chem-
istry of these building blocks provided access to a variety of derivatives including tetrahydrofurans, epoxides and protected amino-
tetraols.
Introduction
Azasugars are small organic compounds that can mimic carbo-
hydrates or their hydrolysis transition states as well as having
many other interesting properties. They are found in nature as
pyrrolidines, piperidines, indolizidines, pyrrolizidines or
nortropane alkaloids with a variety of ring substituents, typical-
ly hydroxy groups, carboxylic acids and amides [1]. The ability
of azasugars, such as the natural product deoxynojirimycin, to
inhibit the activity of a wide range of enzymes has attracted
attention for their potential use as drug candidates [2,3].
Azasugars in clinical use today include Glyset, a licensed drug
for treatment of diabetes type II, and Zavesca, which is used in
treatment of type I Gaucher’s disease and Niemann Pick type C
disease (Scheme 1).
Historically, azasugars were most commonly synthesised from
available carbohydrate starting materials, a strategy that is still
extensively employed today [4,5]. However, a variety of alter-
native synthetic strategies have since been developed, includ-
ing asymmetric and chemoenzymatic methods [2,6-8]. Substi-
tuted endoperoxides have been applied to the synthesis of
substituted cyclopropanes, furans and carbohydrates [9-12].
Inspired by the work of Robinson and co-workers [10-12] we
hypothesised that endoperoxides might provide a new entry to
branched azasugars with novel stereochemistry and substitution
patterns (Scheme 1). Herein we wish to report our preliminary
results in synthesising nitrogen containing endoperoxides as a
potential new source for the divergent synthesis of azasugars.
Beilstein J. Org. Chem. 2017, 13, 644–647.
645
Scheme 1: Top: The natural product deoxynojirimycin and two ana-
logues and marketed drugs Glyset and Zavesca. Bottom: Our synthe-
tic strategy aimed to explore substituted endoperoxides
(e.g. dihydroxylated endoperoxide, box) as key intermediates for the
divergent synthesis of novel azasugars. PG = protection group.
Results and Discussion
We set out to synthesise two diene substrates for a photochemi-
cal [4 + 2]-cycloaddition with singlet oxygen to provide two
different endoperoxides (Scheme 1, n = 1–2). Based on litera-
ture precedent Boc-protection was utilised for the amino group
(Scheme 2) [13,14]. Moreover, the phthalimide-protected com-
pounds were synthesised as UV active analogues that would
facilitate analysis.
Aminoalcohols 1 and 2 were Boc- and Pht-protected under stan-
dard conditions to provide alcohols 3–6 in good yield. Oxida-
tion of alcohol 3 to aldehyde 7 was achieved in moderate yield
using standard Parikh–Doering oxidation conditions [15]. How-
ever, when the same conditions were applied to alcohol 4 it
resulted in a complex mixture. Other oxidation procedures, in-
cluding TPAP [16], Dess–Martin periodinane [17] and TEMPO
[18] were attempted but in all instances complex mixtures were
obtained and none of the desired aldehyde 8 was observed.
Presumably the problems encountered with compound 4 origi-
nates from the ability of the carbamate nitrogen to form a five-
membered hydroxypyrrolidine that can undergo further oxida-
tion [19]. Oxidation of alcohol 5 to give aldehyde 9 was accom-
Scheme 2: Synthesis of Boc- and Pht-protected diene substrates for
endoperoxide synthesis. TBA-Cl = tetrabutylammonium chloride,
NCS = N-chlorosuccinimide.
plished in a low yield using TEMPO, whereas oxidation of 6
using the Parikh–Doering method gave a good yield of alde-
hyde 10. Next, aldehydes 7, 9 and 10 were subjected to a
Mannich reaction using the method by Erkkilä and Pihko to
give the α,β-unsaturated aldehydes 11–13 in good yields [20].
The final step of the diene synthesis was a Wittig reaction with
methyltriphenylphosphonium iodide to provide 14–16. Com-
pound 14 was found to be volatile and thus was only isolated in
a poor yield. For diene 15 the low yield was largely due to
complications with removing the triphenylphosphine oxide side
product. However, at this stage sufficient material of dienes
14–16 was available to proceed to the critical cycloaddition and
dihydroxylation steps and thus no further optimisation was per-
formed.
The cycloaddition reaction of dienes 14–16 with singlet oxygen
was performed in a modified photochemical reactor that had
been fitted with a gas inlet tube at the bottom to allow bubbling
of oxygen through the reaction mixture whilst simultaneously
cooling and irradiating (Scheme 3). During the synthesis of
diene 14 we found that it was volatile and thus we anticipated
problems in the cycloaddition due to the reaction set up. As an-
ticipated when the reaction was performed with the sensitizer
rose bengal the diene was observed to quickly disappear from
the system and only a low yield of endoperoxide 17 was ob-
tained. Due to the many problems encountered with the Boc-
protection strategy it was abandoned at this stage and we turned
our attention to the phthalimide-protected dienes 15,16. When
Beilstein J. Org. Chem. 2017, 13, 644–647.
646
Scheme 4: Dihydroxylation and protection of endoperoxides 18 and 19 to provide novel building blocks 20–23 for azasugar synthesis. Preliminary
exploration of the chemistry of endoperoxides 18–23 was encouraging and gave access to a variety of derivatives.
Scheme 3: Synthesis of endoperoxides 17–19 by [4 + 2]-cycloaddition
of dienes 14–16 with singlet oxygen. The photochemical reactor was
modified with a gas inlet fitted with a filter at the bottom of the reactor,
and the original mercury lamp was replaced with three 100 W halogen
bulbs.
the same reaction was performed with rose bengal on diene 16 a
very low yield of endoperoxide 19 was obtained and most
starting material was recovered (78%) even after prolonged
reaction time (40 h). However, the reaction outcome was
greatly improved by exchanging the sensitizer with tetraphenyl-
porphyrin (TPP) to give a good yield of the desired endoper-
oxide 19. Likewise, diene 15 was converted to the correspond-
ing endoperoxide 18 in good yield using TPP, whereas no prod-
uct was obtained using rose bengal.
With endoperoxides 18 and 19 in hand the stage was set for the
central dihydroxylation reaction that would give access to key
intermediates 20 and 21 (Scheme 4). To our delight dihydroxyl-
ation with potassium osmate in the presence of citric acid was
smooth and gave excellent yields of diols 20 and 21 [11]. Diols
20 and 21 were found to be unstable unless stored at −20 °C.
However, protection of the diol moiety as an acetonide to give
endoperoxides 22 and 23 rendered the compounds stable at
ambient temperature. Compounds 18–23 lend themselves to
undergo a wide range of chemical transformations and are
therefore valuable building blocks that will allow in-depth
exploration of the chemistry of this class of azasugar precursors.
Some preliminary experiments were performed to assess the
possibilities that these building blocks grant.
Endperoxide 19 was epoxidized under standard conditions to
provide the desired epoxide 25 and the anti-diol 26 as a
by-product. Likely, diol 26 is formed by ring-opening of the
epoxide by water present in the mCPBA and the reaction could
be optimised by performing the reaction under anhydrous
conditions. Attempts at cleaving the endoperoxide bond of 20
and 21 by catalytic hydrogenation resulted in rapid decomposi-
tion. However, when the same conditions were applied to
acetonide-protected endoperoxide 23 the desired diol 28 was
obtained, albeit in low yield, with the lactol isomers 29 and 30
as the major product (45%). It is somewhat surprising that the
lactols were formed under these conditions and it is anticipated
that the reaction conditions could be optimised to favour the
desired diol product. Ring contraction of acetonide-protected
endoperoxide 23 by treatment with triphenylphosphine provi-
Beilstein J. Org. Chem. 2017, 13, 644–647.
647
ded ready access to tetrahydrofuran 24 in good yield [21].
Finally, treatment of endoperoxide 23 with Co(salen) gave
ready access to the two lactol isomers 29,30 in quantitative
yield (≈1:1 ratio of isomers) [10,22,23]. Lactol isomers 29,30
could potentially serve as precursors for the formation of substi-
tuted piperidines via reductive amination or be oxidised to yield
lactones or lactam derivatives.
Conclusion
Herein, we report the development of a synthetic strategy using
[4 + 2]-cycloaddition reactions to yield endoperoxides 18–23
that contain a protected primary amine. Such intermediates
serve as useful new building blocks for organic synthesis. Pre-
liminary exploration of the chemistry of these compounds was
encouraging and gave access to a variety of novel protected
azasugar precursors. We conclude that the choice of amine and
dihydroxy protecting groups can have an impact on the success
of the endoperoxide synthesis and its thermal stability, and that
employing phthalimide and acetonide groups for N- and
O-protection, respectively, allow for a range of chemical trans-
formations to be carried out. We are in the process of optimis-
ing and exploring the chemistry of these building blocks and the
results will be reported in due course.
Supporting Information
Supporting Information File 1
Experimental procedures for all compounds; 1H and
13C NMR spectra for novel compounds 13, 16, 18–28.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-63-S1.pdf]
Acknowledgements
The Lundbeck Foundation – Natural Sciences is gratefully ac-
knowledged for financial support.
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Exploring endoperoxides as a new entry for the synthesis of branched azasugars

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Exploring endoperoxides as a new entry for the synthesis of branched azasugars

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