Spiroketals of monosaccharides by dye-sensitized photooxygenation of furyl ketoses

Article abstract of DOI:10.1016/j.tetlet.2013.12.009

[4+2] Cycloaddition of singlet oxygen to suitably substituted furans followed by reduction of the corresponding endoperoxides afforded functionalized enediones which quickly cyclized into the titled spiroketals. The reported method represents a green synthetic one-pot procedure for novel [6,6]-, [5,6]-, and [5,5]-spiroketals of sugars.

Full text of DOI:10.1016/j.tetlet.2013.12.009

Tetrahedron Letters xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Spiroketals of monosaccharides by dye-sensitized photooxygenation
of furyl ketoses q
⇑
Flavio Cermola , Rosalia Sferruzza, Maria Rosaria Iesce
Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario di M. Sant’Angelo, Via Cintia, 80126 Napoli, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
[4+2] Cycloaddition of singlet oxygen to suitably substituted furans followed by reduction of the
corresponding endoperoxides afforded functionalized enediones which quickly cyclized into the titled
spiroketals. The reported method represents a green synthetic one-pot procedure for novel [6,6]-,
[5,6]-, and [5,5]-spiroketals of sugars.
Received 14 October 2013
Revised 27 November 2013
Accepted 4 December 2013
Available online xxxx
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Spiroketals
Photooxygenation
Singlet oxygen
Glycosyl furans
Sugars
n
The spiroketal moiety represents a privileged substructure since
it can be found in many simple or complex natural products char-
acterized by important and assorted biological properties, from
antibiotic to anticancer. Some examples are talaromycins,1 aver-
mectins,2 spongistatin 1,3 and milbemycins.4 Although a wide ar-
ray of ring sizes are possible, the most abundant motifs in Nature
are [6,6]-, [6,5]-, and [5,5]-spiroketals. Accordingly, extensive
investigation on the achievement of spiroketal derivatives is con-
tinuously active and, in addition to the classical route based on
acid-catalyzed ring closure of oxo diols,5 many other elegant strat-
egies6 and asymmetric syntheses7 have been developed. Some ap-
proaches are based on the use of sugars as chiral synthons.8
However, there are few synthetic strategies for spiroketals oxi-
dized at the 2-position (Fig. 1).
O
n
OH
O
n= 1, 2
Figure 1. Spiroketals oxidized at C-2.
BnO
O
BnO
O
BnO
BnO
BnO
BnO
2a
O
O
n-BuLi
THF, 0 °C
BnO
O
BnO
1a
(60 %)
OH
OH
THF, -60 °C
Li
O
Here, the use of sugar-furan based synthesis for novel spiroke-
tals of monosaccharides is reported.
The strategy is based on the easy oxidability of the furan ring
which provides a simple entry to 1,4-dienones. These compounds
can be utilized for a large number of structural elaborations. For in-
O
BnO
Br
Li
BnO
O
O
O
BnO OBn
BnO OBn
O
1b
2b
(58 %)
n-BuLi
stance, oxidation of 2-(a-hydroxyalkyl)furans by m-CPBA or other
THF, -78 °C
oxidizing agents, known as Achmatowicz reaction, leads to the
synthetically useful pyran core through an intramolecular cycliza-
tion of the corresponding enediones.9
OH
O
2b
BnO
O
THF, -78 °C
O
BnO OBn
1,4-Diketones can also be obtained by reaction of furans with
1c
singlet oxygen followed by reduction,10 which represents
a
(50 %)
Scheme 1. Synthesis of furans 1a–c.
q
In the memory of Professor Rachele Scarpati (1927–2013).
⇑
Corresponding author. Tel.: +39 (0)81 674 331; fax: +39 (0)81 674 393.
E-mail address: cermola@unina.it (F. Cermola).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.009
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2
F. Cermola et al. / Tetrahedron Letters xxx (2013) xxx–xxx
stereoselective one-pot method for these versatile functionalized
compounds.11 Recently, the use of 1,4-diketones so obtained pro-
vided simple procedures for novel pyridazine12,13 and pyrazoline13
C-nucleosides, spirocyclic C-nucleosides,14 and new functionalized
exo-glycals.13 The procedure has also been used in the synthesis of
spiro compounds starting from hydroxyalkylfurans.6d
Here, the two-step reaction has been applied to sugar furans
1a–c having a hemiketal function (Scheme 1).
Furans 1a–c were synthetized as shown in Scheme 1. Sugar lac-
tones 2a,b were obtained by Swern oxidation of the corresponding
protected hemiacetals,15 commercially available, and were used as
glycosyl donors toward 2-furyllithium, for 1a,b and 3-furyllithium
(Scheme 2), in a 1:5 molar ratio (Table 1).18 They were in equilib-
rium and, after 48 h in CDCl3 solution, the molar ratio was almost
inverted (5a:6a/2:1). Prompt silica gel chromatography allowed a
partial separation of each isomer. The different stereochemistry
at the new hemiacetal center was evidenced carrying out a Swern
oxidation on a mixture of 5a and 6a which quantitatively led to the
sole expected spiroketal derivative 7a (Scheme 3).19
Noesy experiments allowed to assign the structure 5a with the
(R)-configuration at the new stereocenter (C-2) to the more stable
derivative which was the main product at the equilibrium (Fig. 2).
These experiments also validated the
a-configuration at the su-
gar-ring of both spiroketals, that is probably ensured by a ther-
modynamic control since two anomeric effects are in operation
in a diaxial arrangement,20 as previously reported in similar
cases.21
for 1c. Furan 1a was obtained as a-anomer of a pyranoside struc-
ture,16 while the novel furyl ketoses 1b,c were found and isolated
as open ketone forms.
The dye-sensitized photooxygenation of 1a, followed by reduc-
tion, was carried out at ꢀ60 °C17 and led almost quantitatively to a
diasteromeric mixture of the new chiral [6,6]-spiroketals 5a and 6a
Theoretical calculations22 performed on both stereoisomers
were in agreement with the experimental data suggesting that spi-
roketal 5a is stabilized by an intramolecular hydrogen bond be-
tween the OH at C-2 and the sugar-ring oxygen, which is not
feasible in isomer 6a.
BnO
BnO
BnO
BnO
BnO
BnO
O
O
1. 1O2, - 60 °C
2. Et2S, - 60 °C
O
O
O
Starting from the open structure 1b, the procedure afforded the
new spiroketals 5b and 6b (1:7 molar ratio, respectively), probably
through a double cyclization of the corresponding enedione 4b
(Scheme 4). Compounds 5b and 6b were in equilibrium and after
12 h, in solution at r.t., were present in a 1.5:1 molar ratio. Here,
noesy experiments were unsuccessful and the structure of 5b for
the main product at the equilibrium was suggested by theoretical
calculations22a which found a lower energy for 5b than for 6b of
2.3 kcal/mol. As observed for 5a, the calculated structure for 5b
showed the presence of an intramolecular hydrogen bond between
the OH and the sugar-ring oxygen.
BnO
BnO
BnO
O
BnO
BnO
BnO
+
O
O
OH
1a
OH
OH
5a
6a
1O2
- 60 °C
BnO
BnO
BnO
BnO
O
O
O
O
O
Et2S, - 60 °C
O
BnO
BnO
BnO
3a
BnO
4a
OH
OH
O
Scheme 2. Photooxygenation of 1a and reduction of the endoperoxide 3a.
Finally, the procedure was applied to furan 1c and afforded the
a,b-unsaturated compound 4c which had an unsuitable configura-
tion for cyclization. Anyway, silica gel chromatography promoted
Table 1
One-pot procedure for spiroketals
OHC
O
O
O
i
ii
1
Entry 3
5a
6a
+
Entries 1,2
R
R
O
OH
O
(n)
n= 1, 2
i: 1. 1O2, -60 °C, CH2Cl2; 2. Et2S (1.2 equiv.), -60 °C.
OH
DMSO
Ac2O, r.t.
12 h
BnO
BnO
ii: 1. 1O2, -60 °C, CH2Cl2; 2. Et2S (1.2 equiv.), -60 °C; 3. SiO2, r.t.
O
O
BnO
BnO
O
O
7a
(74 %)
Entry Furyl ketose Spiroketals
BnO
BnO
Yielda (%)
BnO
BnO
O
O
O
O
Scheme 3. Oxidation of a mixture of 5a and 6a; synthesis of 7a.
BnO
BnO
BnO
BnO
O
O
1
1a
80c
OH
OH
6a
5a
1
:
:
5
BnO
BnO
BnO
(2
1)b
O
O
O
O
O
O
BnO
BnO
OBn
H
O
O
O
H OH
OH
OH
OH
NOE
2
3
1b
1c
68c
BnO OBn
BnO OBn
5a
5b
6b
1
(1.5
: 7
:
1)b
Figure 2. Recorded NOE effect in 5a (H-2/H-30).
OHC
OHC
O
BnO
BnO
O
O
OH
1
O
25
BnO OBn
BnO OBn
5c
6c
BnO
O
:
2
O
5b
6b
+
O
O
a
b
c
H
Chromatographic yields.
Molar ratio at the equilibrium at r.t.
The 1H NMR spectrum showed only the presence of the diastereoisomeric
BnO OBn
4b
spiroketals.
Scheme 4. Double cyclization of the enedione 4b.
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F. Cermola et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
7. (a) Wang, X.; Han, Z.; Wang, Z.; Ding, K. Angew. Chem., Int. Ed. 2012, 51, 936–
940; (b) Wilsdorf, M.; Reissig, H.-U. Angew. Chem., Int. Ed. 2012, 51, 9486–9488;
(c) Sun, Z.; Winschel, G. A.; Borovika, A.; Nagorny, P. J. Am. Chem. Soc. 2012, 134,
8074–8077.
8. (a) Méndez-Ardoy, A.; Suàrez-Pereira, E.; Balbuena Oliva, P.; Jiménez Blanco, J.
L.; Ortiz Mellet, C.; Garcìa Fernàndez, J. M. Eur. J. Org. Chem. 2011, 21, 517–528;
(b) Brand, C.; Rauch, G.; Zanoni, M.; Dittrich, B.; Werz, D. B. J. Org. Chem. 2009,
74, 8779–8786; (c) van Hooft, P. A. V.; El Oualid, F.; Overkleeft, H. S.; van der
Marel, G. A.; van Boom, J. H.; Leeuwenburgh, M. A. Org. Biomol. Chem. 2004, 2,
1395–1403; (d) Sharma, G. V. M.; Subhash Chander, R. A.; Goverdhan Reddy, V.;
Ramana Rao, M. H. V.; Kunwar, A. C. Tetrahedron: Asymmetry 2003, 14,
29–30.
1. 1O2, -60 °C
2. Et2S, -60 °C
CHO
OHC
O
CHO
OHC
OH
BnO
BnO
1c
OH
O
BnO OBn
OBn
BnO
4c
SiO2
OHC
O
OHC
OH
BnO
BnO
5c + 6c
CHO
CHO
OH
O
9. Merino, P.; Tejero, T.; Delso, J. I.; Matute, R. Curr. Org. Chem. 2007, 11, 1076–
1091. and references therein.
BnO OBn
BnO OBn
10. (a) Gollnick, K.; Griesbeck, A. Tetrahedron 1985, 41, 2057–2068; (b) Graziano,
M. L.; Iesce, M. R.; Carli, B.; Scarpati, R. Synthesis 1983, 125–126.
11. a Iesce, M. R.; Cermola, F. In CRC Handbook of Organic Photochemistry and
Photobiology; Griesbeck, A. G., Oelgemöller, M., Ghetti, F., Eds.; Springer: New
York, 2012; pp 727–764. Vol. 1; (b) Iesce, M. R.; Cermola, F.; Temussi, F. Curr.
Org. Chem. 2005, 9, 109–139. and references therein.
12. Cermola, F.; Iesce, M. R.; Buonerba, G. J. Org. Chem. 2005, 70, 6503–6505.
13. Cermola, F.; Iesce, M. R. Tetrahedron 2006, 62, 10694–10699.
14. Astarita, A.; Cermola, F.; Iesce, M. R.; Previtera, L. Tetrahedron 2008, 64, 6744–
6748.
8c
Scheme 5. Synthesis of the [5,5]-spiroketals 5c and 6c.
an acid-catalyzed isomerization into the right enedione 8c which
quickly cyclized into the new spiroketals 5c and 6c (Scheme 5).
As suggested by theoretical calculations, to the main product
we tentatively assigned the structure (2S)-6c which was more sta-
ble than (2R)-5c of 2.4 kcal/mol and showed a hydrogen bond be-
tween the OH at C-2 and the oxygen at C-20 of the sugar ring.22a
In conclusion, the work reports a methodology based on a one-
pot process for the synthesis of new chiral [6,6]-, [5,6]-, and [5,5]-
spiroketals of sugars. The aglycone moiety is highly functionalized,
and susceptible of further manipulations, as evidenced by the pre-
liminary successful Swern oxidation to the novel spiroketal 7a.
This extends the scope of the reaction highlighting the possibility
to construct more complex derivatives containing the spiroketal
moiety inside.
15. Overkleeft, H. S.; van Wiltenburg, J.; Pandit, U. K. Tetrahedron 1994, 50, 4215–
4224.
16. Czernecki, S.; Ville, G. J. Org. Chem. 1989, 54, 610–612.
17. Low temperature was necessary because endoperoxides of furans bearing
encumbered groups at 2-position are quite unstable, and rearrange from C–C
to C–O derivatives through a Baeyer–Villiger type-mechanism: (a) Cermola, F.;
Iesce, M. R.; Montella, S. Lett. Org. Chem. 2004, 1, 271–275; (b) Cermola, F.;
Iesce, M. R.; Astarita, A.; Passananti, M. Lett. Org. Chem. 2011, 8, 309–314.
18. General Procedure. A 0.02 M solution of 1 (0.25 mmol) in dry CH2Cl2 was
irradiated at ꢀ60 °C with a halogen lamp (650 W) in the presence of methylene
blue (MB, 1 ꢁ 10ꢀ3 mmol), while dry oxygen was bubbled through the
solution. The progress of each reaction was checked by periodically monitoring
(TLC, or 1H NMR) the disappearance of 1. When the reaction was complete (ca.
90 min), 1.2 equiv of Et2S was added to the crude solution, and the resulting
mixture was kept at ꢀ60 °C for 2 h and then at ꢀ25 °C overnight. Thus, the
solvent and the unreacted Et2S were removed under reduced pressure.
19. Spiroketals 5a and 6a. A 0.02 M solution of 1a (0.25 mmol) was treated as
reported in the general procedure. The 1H NMR spectrum of the residue
showed only the presence of the two diastereisomeric spiroketals 5a and 6a.
Silica gel chromatography (n-hexane/ethyl acetate 7:3 v/v) afforded spiroketal
6a and successively 5a in an overall yield of 80% (124 mg). Compound 5a: IR
Acknowledgments
Financial support from MIUR (PRIN 20109Z2XRJ_007) is grate-
fully acknowledged. NMR experiments were run at the Centro di
Metodologie Chimico-Fisiche, Università di Napoli Federico II.
(CHCl3)
m ;
3425, 1695, 1640, 1601, 1452, 1273 cmꢀ1 1H NMR (CDCl3) d 3.36 (t,
J = 9.3 Hz, 1H, H-6A0), 3.41 (dd, J = 10.4, 9.3 Hz, 1H, H-40), 3.71 (dd, J = 9.3, 1.6
Hz, 1H, H-6B0), 4.09 (dd, J = 10.4, 9.8 Hz, 1H, H-30), 4.15 (br s, 1H, OH), 4.27 (d,
J = 9.8 Hz, 1H, H-20), 4.48 (s, 2 H, CH2 of Bn), 4.50 (d, J = 11.5 Hz, 1H, CH of Bn),
4.55 (m, 1H, H-50), 4.63 (d, J = 10.9 Hz, 1H, CH of Bn), 4.78 (d, J = 10.9 Hz, 1H, CH
of Bn), 4.83 (d, J = 10.9 Hz, 1H, CH of Bn), 4.90 (m, 2 H, CH2 of Bn), 5.58 (dd,
J = 12.7, 3.3 Hz, 1H, H-2), 6.18 (d, J = 10.3 Hz, 1H, H-4), 6.92 (dd, J = 10.3, 3.3 Hz,
1H, H-3), 7.15–7.38 (m, 20 H, 4ꢁ Ph); 13C NMR (CDCl3) d 69.1 (t), 71.9 (d), 73.4
(t), 75.0 (t), 75.5 (t), 75.8 (t), 78.4 (d), 78.5 (d), 83.2 (d), 88.8 (d), 97.7 (s), 124.8
(d), 127.7 (d), 127.8 (d), 127.9 (d), 128.0 (d), 128.2 (d), 128.4 (d), 137.4 (s),
Supplementary data
Supplementary data (1H–1H COSY and NOESY experiments, het-
eronuclear chemical shift correlations by HMQC pulse sequences,
1H and 13C NMR for new compounds) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.12.009.
137.7 (s), 138.0 (s), 138.4 (s), 145.7 (d), 188.7 (s). Compound 6a: IR (CHCl3)
m
3432, 1695, 1643, 1600, 1450, 1276 cmꢀ1 1H NMR (CDCl3) d 3.68 (m, 3 H, H-
;
60A, H-60B and H-4), 3.85 (d, J = 10.8 Hz, 1H, OH), 4.04-4.17 (m, 3 H, H-20, H-30
and H-50), 4.47–4.57 (m, 4H, CH2 of Bn), 4.79 (d, J = 10.4 Hz, 1H, CH of Bn), 4.84
(d, J = 10.9 Hz, 1H, CH of Bn), 4.90 (s, 2H, CH2 of Bn), 5.65 (br d, J = 10.8 Hz, 1H,
H-2), 6.19 (dd, J = 10.4, 1.2 Hz, 1H, H-4), 6.87 (dd, J = 10.4, 1.6 Hz, 1H, H-3),
7.15–7.38 (m, 20 H, 4ꢁ Ph); 13C NMR (CDCl3) d 68.5 (t), 73.4 (t), 74.0 (t), 75.0
(d), 75.7 (t), 75.9 (t), 78.0 (d), 79.5 (d), 82.6 (d), 87.7 (d), 98.3 (s), 127.0 (d),
127.7 (d), 127.8 (d), 128.0 (d), 128.3 (d), 128.4 (d), 137.3 (s), 137.9 (s), 138.1 (s),
138.4 (s), 147.9 (d), 188.6 (s). Anal. Calcd for C38H38O8 on a diastereomeric
mixture of 5a and 6a: C, 73.29; H, 6.15. Found: C, 73.12; H, 6.01. Spiroketal 7a.
A 0.5 mmol of a mixture of spiroketals 5a and 6a in ca. 1.3:1 molar ratio was
dissolved in dry DMSO (1.4 mL). Then, acetic anhydride (0.8 mL) was added
and the resulting solution was stirred at r.t. under argon atmosphere. After ca
12 h the reaction was quenched by adding H2O (ca. 10 mL). The organic layer
was extracted with CHCl3, washed with H2O (5 ꢁ 10 mL), dried on MgSO4, and
filtered. Then, the solvent was removed under reduced pressure and the
residue was chromatographed on silica gel (n-hexane/ethyl acetate 75:15 v/v)
References and notes
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affording spiroketal 7a as oil in ca. 74% yield (230 mg). IR (CHCl3)
m 1745, 1690,
1600, 1440, 1260 cmꢀ1 1H NMR (CDCl3) d = 3.64 (dd, J = 11.3, 1.8 Hz, 1H, H-
;
60A), 3.77 (dd, J = 11.3 Hz, 3.9, 1H, H-60B), 3.82 (t, J = 9.4 Hz, 1H, H-40), 4.08 (d,
J = 9.7 Hz, 1H, H-20), 4.20 (bt, J = 9.4 Hz, 2 H, H-30 and H-50), 4.48 (d, J = 12.6 Hz,
1H, CH of Bn), 4.51 (d, J = 11.5 Hz, 1H, CH of Bn), 4.58 (d, J = 12.6 Hz, 1H, CH of
Bn), 4.61 (d, J = 10.0 Hz, 1H, CH of Bn), 4.84-4.90 (m, 4 H, 2ꢁ CH2 of Bn), 6.70 (d,
J = 10.3 Hz, 1H, H-4), 6.83 (d, J = 10.3 Hz, 1H, H-3), 7.14-7.34 (m, 20 H, 4ꢁ Ph);
13C NMR (CDCl3) d = 67.9 (t), 73.3 (t), 74.7 (d), 75.0 (t), 75.2 (t), 75.8 (t), 77.0 (d),
79.8 (d), 82.1 (d), 101.7 (s), 127.5 (d), 127.6 (d), 127.7 (d), 128.3 (d), 135.0 (d),
136.9 (d), 137.4 (s), 137.9 (s), 138.2 (s), 159.2 (s), 187.5 (s). Anal. Calcd for
C38H36O8: C, 73.53; H, 5.85. Found: C, 73.41; H, 5.76.
Please cite this article in press as: Cermola, F.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.12.009

4
F. Cermola et al. / Tetrahedron Letters xxx (2013) xxx–xxx
20. (a) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Pergamon
Press: New York, 1983; (b) Kirby, A. J. The Anomeric Effect and Related
Stereoelectronic Effects at Oxygen; Springer-Verlag: New York, 1983.
performed starting from minimized conformers (conformational analysis by
MMFF-molecular mechanics). Energies were calculated running single points
by B3LYP/6.31G⁄ method.; (b) Calculations found that (2R)-5a is more stable
than (2S)-6a of 3.7 kcal/mol.
21. Perron, F.; Albizati, K. F. J. Org. Chem. 1989, 54, 2044–2047.
22. (a) Theoretical calculations were carried out by SPARTAN 008 Quantum
Mechanics Program. The geometric optimizations (method: HF/3-21G) were
Please cite this article in press as: Cermola, F.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.12.009