Trisequential photooxygenation reaction: Application to the synthesis of carbasugars

Article abstract of DOI:10.1021/ol401823m

4,5-Dimethylenecyclohex-1-ene was subjected to a photooxygenation reaction to introduce oxygen functionalities. The endoperoxide obtained underwent an ene-reaction to form hydroperoxides with 1,3-diene structures. Further addition of singlet oxygen to the

Full text of DOI:10.1021/ol401823m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Trisequential Photooxygenation Reaction:
Application to the Synthesis of
Carbasugars
000–000
,
†
†
Arif Baran,* Gokay Aydin, Tahir Savran, Ertan Sahin, and Metin Balci*
†
‡
,§
Department of Chemistry, Sakarya University, 54100 Sakarya, Turkey, Department of
Chemistry, Ataturk University, 25240 Erzurum, Turkey, and Department of Chemistry,
Middle East Technical University, 06800 Ankara, Turkey
mbalci@metu.edu.tr; abaran@sakarya.edu.tr
Received June 28, 2013
ABSTRACT
4,5-Dimethylenecyclohex-1-ene was subjected to a photooxygenation reaction to introduce oxygen functionalities. The endoperoxide obtained
underwent an ene-reaction to form hydroperoxides with 1,3-diene structures. Further addition of singlet oxygen to the diene units resulted in the
formation of tricyclic hydroperoxides having three oxygens in the molecule. Cleavage of the oxygenꢀoxygen bonds followed by epoxidation of
the remaining CꢀC double bond and concomitant ring-opening reaction furnished the isomeric carbasugars.
Structural entities having polyhydroxylated cyclohexa-
noid cores are widely distributed in nature, and they have,
in recent decades, attracted interest among chemists due to
their significant biological properties and diverse synthetic
intermediates. Cyclitols are involved in glycosidase inhi-
bition, intercellular communication, phosphate storage,
protein anchoring, etc. Therefore, glycosidase inhibitors
are generally regarded as promising candidates for the
2
development of new drugs. Carbasugars, generated by
replacing the endocyclic oxygen atom in monosacca-
rides, are thought to be more viable drug candidates than
natural sugars, since they are stable under hydrolytic
1
3
conditions.
Recently, we synthesized some new carbasugar deriv-
†
Sakarya University.
Ataturk University.
Middle East Technical University.
4
atives and showed that they inhibit the activity of
‡
§
R-glycosidase and increase the activity of R-amylase.
Furthermore, we prepared various branched Carbahexo-
pyranose derivatives, which showed strong inhibition for
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J. Org. Chem. 2012, 77, 7401–7410. (e) Ekmekci, Z.; Balci, M. Eur. J.
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Chem. Rev. 2011, 111, 4223–4258. (g) Kilbas, B.; Balci, M. Tetrahedron
5
R-glycosidase. Here, we describe the synthesis of new
2
011, 67, 2355–2389. (h) Arjona, O.; Gomez, A. M.; Lopez, J. C.;
(2) For recent reviews on carbasugars, see: (a) Soengas, R. G.; Otero,
J. M.; Estevez, A. M.; Rauter, A. P.; Cachatra, V.; Estevez, J. C.;
Estevez, R. J. Carbohydr. Chem. 2012, 38, 263–302. (b) Jarosz, S.;
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Fransisco, 1965.
1
0.1021/ol401823m r XXXX American Chemical Society

sensitizer afforded the endoperoxide 5 in 86% yield.
However, when the reaction was carried out at rt for
Scheme 1. Synthesis of the Diene 4
40 h, the reaction proceeded further and the endoperoxide
5 formed initially underwent a cascade photooxygenation
reaction to form two regioisomeric tricyclic bis-endoper-
oxides 6 (50%) and 7 (8%) beside the aromatization
1
1
product 8 (21%). The products were separated by col-
umn chromatography.
Scheme 2. Synthesis of the Bis-endoperoxides 6 and 7
branched carbasugars where we applied a tandem reaction
of singlet oxygen to 4,5-dimethylenecyclohex-1-ene (4).
The starting material, 4,5-dimethylenecyclohex-1-ene
(
tion of maleic anhydride to in situ generated butadiene
4), was synthesized in four steps starting with the addi-
6
(
the diol 2, whose OH groups were iodinated with I , in the
Scheme 1). Reduction of 1 with LiAlH in THF afforded
4
7
2
8
presence of imidazole and PPh to give 3. The diiodide 3
was subjected to an elimination reaction of 2 mol of HI
3
9
with KOH in methanol to afford the diene 4 in almost
1
The structures of 6 and 7 were assigned by H and
13
C
NMR spectra. The 300 MHz H NMR spectrum of 6 in
quantitative yield.
Our route to carbasugars was based on a photooxygena-
tion reaction of the diene 4 (Scheme 2). Photooxygena-
1
CDCl exhibits two doublet of doublets at δ 6.83 (J = 8.5
3
1
0
and 6.1 Hz) and δ 6.18 (J = 8.5 and 1.5 Hz). The main
coupling (8.5 Hz) is in agreement with the cis-configuration
of the double bond protons. Further splittings arise from
coupling with the bridgehead proton H-7. The methylene
protons next to the hydroperoxide group resonate as an
AB-system at δ 2.08 and δ 1.94 ppm. Both parts of this
system show further coupling with the bridge-head proton
H-7. The structure of the regioisomer 7 was established by
NMR data. Further confirmation was achieved by single
crystal X-ray analysis (Figure 1). The molecule 7 crystal-
tion of diene 4 in methylene chloride (500 W, projection
lamp, 25 min) at 0 °C using tetraphenylporphyrin as a
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White, J. C.; Kociok-K o€ hn, G.;Lloyd, M. D.;Wells, A.;Arnot, T. C.;Lewis,
S. E. Tetrahedron 2013, 69, 5989–5997. (b) Tripathy, S.; Chattopadhyay, A.
Tetrahedron: Asymmetry 2012, 23, 1423–1429. (c) Palframan, M. J.; Kociok-
K o€ hn,G.;Lewis,S.E. Chem.;Eur. J. 2012, 18, 4766–4774. (d) Rej, R.; Jana,
N.; Kar, S.; Nanda, S. Tetrahedron: Asymmetry 2012, 23, 364–372. (e)
Mehta, G.; Mohanrao, R.; Katukojvala, S.; Landais, Y.; Sen, S.
Tetrahedron Lett. 2011, 52, 2893–2897. (f) Frau, I.; Di Bussolo, V.;
Favero, L.; Pineschi, M.; Crotti, P. Chirality 2011, 23, 820–826. (g)
Pilgrim, S.; Kociok-K o€ hn, G.; Lloyd, M. D.; Lewis, S. E. Chem.
Commun. 2011, 47, 4799–4801. (h) Shing, T. K. M.; Chen, Y.; Ng,
W. L. Synlett 2011, 1318–1320. (i) Frigell, J.; Cumpstey, I. Beilstein J.
Org. Chem. 2010, 6, 1127–1131. (j) Leermann, T.; Oliver, B.; Podeschwa,
M. A. L.; Pfueller, U.; Altenbach, H.-J. Org. Biomol. Chem. 2010, 8,
lized in the monoclinic space group P2 /n with Z = 4.
1
3
2
965–3974. (k) Shan, M.; O’Doherty, G. A. Org. Lett. 2010, 12, 2986–
989. (l) Salamci, E. Tetrahedron 2010, 66, 4010–4015. (m) Paquette,
L. A.; Moura-Letts, G.; Wang, G. P. J. Org. Chem. 2009, 74, 2099–2107.
4) Kishali, N. H.; Dogan, D.; Sahin, E.; Gunel, A.; Kara, Y.; Balci,
M. Tetrahedron 2011, 67, 1193–1200.
5) (a) Aydin, G.; Savran, T.; Akta -s , F.;Baran, A.;Balci, M. Org. Biomol.
(
(
Chem. 2013, 11, 1511–1524. (b) Baran, A.; Bekarlar, M.; Aydin, G.;
Nebioglu, M.; Sahin, E.; Balci, M. J. Org. Chem. 2012, 77, 1244–1250. (c)
Baran, A.; Gunel, A.; Balci, M. J. Org. Chem. 2007, 73, 4370–4375.
(6) (a) Goodridge, R. J.; Hambley, T. W.; Ridley, D. D. Aust. J.
Chem. 1986, 39, 591–604. (b) Hall, H. K., Jr.; Nogues, P.; Rhoades,
J. W.; Sentman, R. C.; Detar, M. J. Org. Chem. 1982, 47, 1451–1455.
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1966, 803–807. (c) Von Langen, D. J.; Tolman, R. L. Tetrahedron:
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Kurihara, M.; Doi, M.; Suemune, H.; Tanaka, M. Helv. Chem. Acta
012, 95, 1694–1713. (b) Blakemore, D. C.; Bryans, J. S.; Carnell, P.;
Figure 1. ORTEP diagram of 7. Thermal ellipsoids are shown at
40% probability level.
(
2
Carr, C. L.; Chessum, N. E. A.; Field, M. J.; Kinsella, N.; Osborne, S. A.;
Warren, A. N.; Williams, S. C. Bioorg. Med. Chem. J. 2010, 20, 461–464.
For the formation of these bis-endoperoxides 6 and 7, we
suggest the following mechanism (Scheme 3). Dimethyl-
enecyclohexene 4 first undergoes a cycloaddition reaction
(
c) Tanaka, M.; Anan, K.; Demizu, Y.; Kurihara, M.; Doi, M.;
Suemune, H. J. Am. Chem. Soc. 2005, 127, 11570–11571.
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B. W.; Wege, W.; Allan, H.; White, A. H. Eur. J. Org. Chem. 2007, 1184–
(
1195. (b) Bailey, W. J.; Rosenberg, J. J. Am. Chem. Soc. 1955, 77, 73–75.
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1358.
B
Org. Lett., Vol. XX, No. XX, XXXX

with singlet oxygen to give the dihydrodioxine derivative
with a cyclohexa-1,4-diene structure. The cyclohexa-1,4-
dioxine rings. Hydroperoxides 10 and 13 with 1,3-diene
faces have no plane of symmetry, and their 1,3-diene faces
are inequivalent, so the third equivalent of singlet oxygen
adds to the diene units from the less crowded face of the
molecule to give 6 and 7. To the best of our knowledge, this
is thefirst reported reactionwhere 3 equiv of singlet oxygen
5
1
2
diene unit in 5 undergoes an ene-reaction with singlet
oxygen. The two alkenes in 5 are inequivalent, and singlet
oxygen can attack either one. When the singlet oxygen
attacks the more substituted double bond, two diastereo-
isomeric perepoxides 11 and 12 may be formed. The prod-
uct distribution shows the exclusive formation of the
perepoxide 11, where the pendent oxygen can abstract
the allylic hydrogen from one of the methylene groups
next to the double bond and form the hydroperoxide 13.
Probably, the repulsive interaction between the lone pairs
of the oxygen atoms in the dioxine unit and the incoming
oxygen molecule hinders the formation of 12. Recently, we
demonstrated that singlet oxygen attacks exclusively the
more substituted double bond in 1,2-dimethylcyclohexa-
1
4
are incorporated in a cascade process.
Scheme 4. Synthesis of the Carbasugars 19 and 22
1
3
1
,4-diene. However, in the case of 5, the less substituted
double bond was also attacked in a ratio of 1:6. If singlet
oxygen attacks the sterically less crowded double bond in
5, the perepoxide 9 can be formed, which would then
rearrange to the hydroperoxide 10.
Scheme 3. Proposed Mechanism for the Formation of the
Endoperoxides 6 and 7
The highly functionalized endoperoxides 6 and 7 are
ideal substrates for the synthesis of carbasugars. For that
reason the peroxide linkages in 6 were reduced by thiourea
under very mild conditions, followed by acetylation of
the primary and secondary hydroxyl groups to give 14
(
Scheme 4). Since only oxygenꢀoxygen bonds breakin this
reaction, the configuration of all carbon atoms is pre-
served. The triacetate 14 was reacted with m-chloroper-
benzoic acid to give a single epoxide 15 in 67% yield as well
as the tetrol 17 (21%), which is probably formed by the ring-
opening reaction of the initially formed exo-isomer 16. The
configuration of the epoxide 15 was determined by measur-
ing the coupling constant between the acetoxy proton H5
and epoxide proton H (J = 2.1 Hz) in CDCl3.
The stabilizing interaction of pendent oxygen with two
allylic hydrogens on the same side of the double bond is
responsible for the formation of endo-perepoxide 9. This
siteselectivity of singletoxygenwas rationalized in terms of
the electrophilic character of singlet oxygen.
6
5,6
The geometry optimized structure (DFT, B3LYP/
6
-31þG** level) of the epoxide 15 shows a dihedral angle
of 54°, which is in agreement with the observed coupling
In5, the reactivityofthe moresubstituteddoublebond is
decreased due to the inductive effect of oxygen atoms in
(
14) For tandem singlet oxygenation reactions, see: (a) Griesbeck,
A. G.; de Kiff, A. Org. Lett. 2013, 15, 2073–2075. (b) Montagnon, T.;
Tofi, M.; Vassilikogiannakis, G. Acc. Chem. Res. 2008, 41, 1001–1011.
(c) Kishali, N.; Sahin, E.; Kara, Y. Org. Lett. 2006, 8, 1791–1793. (d)
Salamci, E.; Secen, H.; Sutbeyaz, Y.; Balci, M. J. Org. Chem. 1997, 62,
2453–2457. (e) Zhang, X.; Lin, F.; Foote, C. S. J. Org. Chem. 1995, 60,
1333–13338. (f) Burns, P. A.; Foote, C. S.; Mazur, S. J. Org. Chem. 1976,
41, 899–907. (g) Gollnick, K. Adv. Photochem. 1968, 6, 1–122.
(
12) (a) Griesbeck, A. G.; Goldfuss, B.; Leven, M.; de Kiff, A.
Tetrahedron Lett. 2013, 54, 2831. (b) Stratakis, M.; Orfanopoulos, M.
Tetrahedron 2000, 56, 1595–1615.
(13) Yardimci, S. D.; Kaya, N.; Balci, M. Tetrahedron 2006, 62,
10633–10638.
Org. Lett., Vol. XX, No. XX, XXXX
C

We assumed that the second isomer, anti-isomer 16, was
also formed during the epoxidation reaction. Because of
the anti-configuration of the neighboring acetate, this
epoxide 16 may undergo a ring-opening reaction to afford
17. The tetrol 17 was transformed into the corresponding
pentatacetate for full characterization of the structure.
Deacetylation of pentaacetate 21 with ammonia resulted
in the formation of an isomeric hexol, 22. The structure of
21 was confirmed by NMR spectral methods. Further-
more, a poor quality X-ray determination provided sup-
port for the structure.
In summary, with relatively little synthetic effort, we
achieved the synthesis of two isomeric carbasugar deriva-
tives, 19 and 22, starting from 4,5-dimethylene-cyclohex-1-
ene. The complex stereochemistry was introduced in a
single step, by means of a photooxygenation reaction. To
the best of our knowledge, this is the first case in which
singlet oxygen undergoes three cascade reactions. Cleav-
age of the peroxide linkages in 6 followed by oxidation of
the double bond and ring-opening reaction resulted in the
formation of two new carbasugars. Further applications of
singlet oxygen to the synthesis of carbasugars with com-
plex structures are currently in progress.
Figure 2. ORTEP diagram of 19. Thermal ellipsoids are shown
at the 50% probability level.
constant. The sulfuric acid catalyzed reaction of epoxy
triacetate 15 in water followed by acetylation resulted in
opening of the epoxide ring to afford pentaacetate 18.
Deacetylation of18withammoniagavethe hexol19, a new
carbasugar, in 95% yield. The structure of 19 was con-
firmed by single crystal X-ray analysis (Figure 2). The
molecule 19 crystallized from water in the monoclinic
Acknowledgment. We are indebted to the Scientific and
Technological Research Council of Turkey (TUBITAK,
Grant No. 109T817), the Departments of Chemistry at
Sakarya University and Middle East Technical University,
and the Turkish Academy of Sciences (TUBA) for finan-
cial support of this work.
space group P2 /c with Z = 4. This configurational
1
assignment shows that the epoxide ring in 15 under-
went a trans ring-opening reaction without any anchimeric
assistance. To prove this outcome, the acetate groups in 15
were removed with ammonia in methanol to give 20. Acid
catalyzed ring opening of 21 followed by acetylation af-
forded 18, which was identical to the compound obtained by
hydrolysis of 15. With this chemical reaction, noninvolve-
ment of the acetates in 15 in the ring-opening reaction was
further proven. This may be attributed to the cis-configura-
tion of the acetate group next to the epoxide ring in 15.
The stereochemical course of the epoxidation of 14 may
be syn or anti with respect to the adjacent acetoxy group.
Supporting Information Available. Experimental con-
ditions, spectroscopic data (1D and 2D NMR spectra),
crystallographic information (CIF) of the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX