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

Article abstract of DOI:10.3762/bjoc.13.63

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 amino-tetraols.

Full text of DOI:10.3762/bjoc.13.63

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:
Beilstein J. Org. Chem. 2017, 13, 644–647.
Department of Drug Design and Pharmacology, University of
Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark
doi:10.3762/bjoc.13.63
Received: 16 December 2016
Accepted: 13 March 2017
Published: 03 April 2017
Email:
Daniel Sejer Pedersen* - daniel.pedersen@sund.ku.dk
* Corresponding author
Associate Editor: S. Flitsch
Keywords:
© 2017 Domeyer et al.; licensee Beilstein-Institut.
License and terms: see end of document.
azasugar; carbohydrate; cycloaddition; endoperoxide; photochemistry
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- Historically, azasugars were most commonly synthesised from
hydrates or their hydrolysis transition states as well as having available carbohydrate starting materials, a strategy that is still
many other interesting properties. They are found in nature as extensively employed today [4,5]. However, a variety of alter-
pyrrolidines, piperidines, indolizidines, pyrrolizidines or native synthetic strategies have since been developed, includ-
nortropane alkaloids with a variety of ring substituents, typical- ing asymmetric and chemoenzymatic methods [2,6-8]. Substi-
ly hydroxy groups, carboxylic acids and amides [1]. The ability tuted endoperoxides have been applied to the synthesis of
of azasugars, such as the natural product deoxynojirimycin, to substituted cyclopropanes, furans and carbohydrates [9-12].
inhibit the activity of a wide range of enzymes has attracted Inspired by the work of Robinson and co-workers [10-12] we
attention for their potential use as drug candidates [2,3]. hypothesised that endoperoxides might provide a new entry to
Azasugars in clinical use today include Glyset, a licensed drug branched azasugars with novel stereochemistry and substitution
for treatment of diabetes type II, and Zavesca, which is used in patterns (Scheme 1). Herein we wish to report our preliminary
treatment of type I Gaucher’s disease and Niemann Pick type C results in synthesising nitrogen containing endoperoxides as a
disease (Scheme 1).
potential new source for the divergent synthesis of azasugars.
644

Beilstein J. Org. Chem. 2017, 13, 644–647.
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-
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- pound 14 was found to be volatile and thus was only isolated in
cal [4 + 2]-cycloaddition with singlet oxygen to provide two a poor yield. For diene 15 the low yield was largely due to
different endoperoxides (Scheme 1, n = 1–2). Based on litera- complications with removing the triphenylphosphine oxide side
ture precedent Boc-protection was utilised for the amino group product. However, at this stage sufficient material of dienes
(Scheme 2) [13,14]. Moreover, the phthalimide-protected com- 14–16 was available to proceed to the critical cycloaddition and
pounds were synthesised as UV active analogues that would dihydroxylation steps and thus no further optimisation was per-
facilitate analysis.
formed.
Aminoalcohols 1 and 2 were Boc- and Pht-protected under stan- The cycloaddition reaction of dienes 14–16 with singlet oxygen
dard conditions to provide alcohols 3–6 in good yield. Oxida- was performed in a modified photochemical reactor that had
tion of alcohol 3 to aldehyde 7 was achieved in moderate yield been fitted with a gas inlet tube at the bottom to allow bubbling
using standard Parikh–Doering oxidation conditions [15]. How- of oxygen through the reaction mixture whilst simultaneously
ever, when the same conditions were applied to alcohol 4 it cooling and irradiating (Scheme 3). During the synthesis of
resulted in a complex mixture. Other oxidation procedures, in- diene 14 we found that it was volatile and thus we anticipated
cluding TPAP [16], Dess–Martin periodinane [17] and TEMPO problems in the cycloaddition due to the reaction set up. As an-
[18] were attempted but in all instances complex mixtures were ticipated when the reaction was performed with the sensitizer
obtained and none of the desired aldehyde 8 was observed. rose bengal the diene was observed to quickly disappear from
Presumably the problems encountered with compound 4 origi- the system and only a low yield of endoperoxide 17 was ob-
nates from the ability of the carbamate nitrogen to form a five- tained. Due to the many problems encountered with the Boc-
membered hydroxypyrrolidine that can undergo further oxida- protection strategy it was abandoned at this stage and we turned
tion [19]. Oxidation of alcohol 5 to give aldehyde 9 was accom- our attention to the phthalimide-protected dienes 15,16. When
645

Beilstein J. Org. Chem. 2017, 13, 644–647.
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
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 acetonide-protected endoperoxide 23 the desired diol 28 was
very low yield of endoperoxide 19 was obtained and most obtained, albeit in low yield, with the lactol isomers 29 and 30
starting material was recovered (78%) even after prolonged as the major product (45%). It is somewhat surprising that the
reaction time (40 h). However, the reaction outcome was lactols were formed under these conditions and it is anticipated
greatly improved by exchanging the sensitizer with tetraphenyl- that the reaction conditions could be optimised to favour the
porphyrin (TPP) to give a good yield of the desired endoper- desired diol product. Ring contraction of acetonide-protected
oxide 19. Likewise, diene 15 was converted to the correspond- endoperoxide 23 by treatment with triphenylphosphine provi-
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.
646

Beilstein J. Org. Chem. 2017, 13, 644–647.
7. Karjalainen, O. K.; Koskinen, A. M. P. Org. Biomol. Chem. 2011, 9,
1231–1236. doi:10.1039/C0OB00747A
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.
8. Compain, P.; Chagnault, V.; Martin, O. R. Tetrahedron: Asymmetry
2009, 20, 672–711. doi:10.1016/j.tetasy.2009.03.031
9. Avery, T. D.; Greatrex, B. W.; Sejer Pedersen, D.; Taylor, D. K.;
Tiekink, E. R. T. J. Org. Chem. 2006, 73, 2633–2640.
doi:10.1021/jo7024256
10.Pedersen, D. S.; Robinson, T. V.; Taylor, D. K.; Tiekink, E. R. T.
J. Org. Chem. 2009, 74, 4400–4403. doi:10.1021/jo900392y
11.Robinson, T. V.; Taylor, D. K.; Tiekink, E. R. T. J. Org. Chem. 2006, 71,
7236–7244. doi:10.1021/jo060949p
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.
12.Robinson, T. V.; Pedersen, D. S.; Taylor, D. K.; Tiekink, E. R. T.
J. Org. Chem. 2009, 74, 5093–5096. doi:10.1021/jo900669u
13.James, T.; Simpson, I.; Grant, J. A.; Sridharan, V.; Nelson, A. Org. Lett.
2013, 15, 6094–6097. doi:10.1021/ol402988s
14.Pedersen, D. S.; Taylor, D. K.; Tiekink, E. R. T.
Acta Crystallogr., Sect. E 2007, 63, o4301.
doi:10.1107/S1600536807049252
15.Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89,
5505–5507. doi:10.1021/ja00997a067
16.Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639–666. doi:10.1055/s-1994-25538
17.Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
doi:10.1021/jo00170a070
18.Delfourne, E.; Kiss, R.; Le Corre, L.; Dujols, F.; Bastide, J.;
Collignon, F.; Lesur, B.; Frydman, A.; Darro, F. J. Med. Chem. 2003,
46, 3536–3545. doi:10.1021/jm0308702
19.Xiao, X.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M.
Bioorg. Med. Chem. 2004, 12, 5147–5160.
doi:10.1016/j.bmc.2004.07.027
Supporting Information
20.Erkkilä, A.; Pihko, P. M. J. Org. Chem. 2006, 71, 2538–2541.
doi:10.1021/jo052529q
Supporting Information File 1
21.Greatrex, B. W.; Taylor, D. K. J. Org. Chem. 2004, 69, 2577–2579.
doi:10.1021/jo030330c
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]
22.Avery, T. D.; Haselgrove, T. D.; Taylor, D. K.; Tiekink, E. R. T.;
Avery, T. D.; Rathbone, T. J. Chem. Commun. 1998, 333–334.
doi:10.1039/A707360G
23.Avery, T. D.; Taylor, D. K.; Tiekink, E. R. T. J. Org. Chem. 2000, 65,
5531–5546. doi:10.1021/jo0002240
Acknowledgements
The Lundbeck Foundation – Natural Sciences is gratefully ac-
License and Terms
knowledged for financial support.
This is an Open Access article under the terms of the
Creative Commons Attribution License
References
1. Winchester, B. G. Tetrahedron: Asymmetry 2009, 20, 645–651.
(http://creativecommons.org/licenses/by/4.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
doi:10.1016/j.tetasy.2009.02.048
2. Horne, G. In Carbohydrates as Drugs; Seeberger, P. H.;
Rademacher, C., Eds.; Springer International Publishing: Cham, 2014;
pp 23–51.
3. Horne, G.; Wilson, F. X.; Tinsley, J.; Williams, D. H.; Storer, R.
Drug Discovery Today 2011, 16, 107–118.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
doi:10.1016/j.drudis.2010.08.017
(http://www.beilstein-journals.org/bjoc)
4. Tamayo, J. A.; Franco, F.; Lo Re, D. Synlett 2010, 1323–1326.
doi:10.1055/s-0029-1219827
The definitive version of this article is the electronic one
which can be found at:
5. Petakamsetty, R.; Jain, V. K.; Majhi, P. K.; Ramapanicker, R.
Org. Biomol. Chem. 2015, 13, 8512–8523. doi:10.1039/C5OB01042J
6. Marjanovic, J.; Ferjancic, Z.; Saicic, R. N. Tetrahedron 2015, 71,
6784–6789. doi:10.1016/j.tet.2015.07.036
doi:10.3762/bjoc.13.63
647