Angewandte
Communications
Chemie
such bisperoxides are readily formed in the reactions of 1,3-
Table 1: Ozone-free synthesis of ozonides 2a–j, 3a–j, and mixtures
[
a]
[4a,b]
thereof from diketones 1a–j and H O .
diketones (Figure 3).
However, this situation starts to
2
2
change as the bridge gets longer. In the [2.2.2]tetraoxabicy-
clooctane, two of the anomeric interactions are considerably
ꢀ
1
weakened (to 8.7 kcalmol ; Figure 3). A truly dramatic
effect is observed for the [3.2.2]tetraoxabicyclononane skel-
eton, in which two of the n !s*
interactions nearly
disappear (3.4 and 1.0 kcalmol ) because of the large
deviations in the OOCO dihedral from the ideal value of
O
C–O
ꢀ1
6
08 (33 and 258, respectively).
Encouraged by the large stereoelectronic differences
between the otherwise very similar bicyclic bisperoxides and
earlier reports of the higher stabilities of ozonides obtained by
[
11]
different routes,
we investigated the reactivity of 1,5-
diketones and H O . There are only a few scattered reports of
2
2
[
12]
[13]
this process in the presence of P O , V O , and peracetic
acid with borone trifluoride. More recently, diketones of
the oleanane family were transformed into ozonides by the
2
5
2
5
[
14]
[
15]
use of a CH COOOH/H O system. There is one report of
3
2
2
ozonide formation in low yield from 2,6-heptanedione and
ꢀ
2
[16]
H O in the gas phase at 10 torr.
Finally, an isolated
2
2
example of ozonide synthesis from an acetal of 1,5-diketo-
[
2e]
[17]
ne was followed by a recent study, in which the hidden
,5-dicarbonyl functionality of artemisinin was transformed
1
into a mixed ketoacetal and then into a pair of stereoisomeric
ozonides through a reaction with H O under the catalysis of
2
2
HCl. We found earlier that the acid-catalyzed reaction of
branched b’,d-triketones with H O yielded ozonides, but in
2
2
a mixture with bridged tetraoxanes and tricyclic monoperox-
[
6b,18]
ides.
To our delight, the reaction of 1,5-diketones with H O in
2
2
the presence of a Brønsted or Lewis acid led cleanly and
efficiently to the exclusive formation of ozonides, even in the
case of substrates with alkene or alkyne functionalities, which
are not compatible with the classical ozone-based approach to
ozonides. No bisperoxides were observed with these dicar-
bonyl substrates (Table 1). Furthermore, an ozonide could be
formed from a 1,5-ketoaldehyde and H O . Convenient
2
2
conditions for the peroxidation of 1,5-dicarbonyl compounds
1
a–n involve the combination of ethereal H O with either
2 2
BF ·Et O or H SO as a promoter.
3
2
2
4
We tested the scope and limitations of this ring-assembly
1
5
process by introducing substituents R –R at different posi-
tions of the 1,5-dicarbonyl compound 1. The lack of ozonide
formed in the reaction of 2,5-heptanedione and inefficient
cyclization (18% by NMR spectroscopy) of 4-methylheptane-
[
a] Yields are for the isolated individual compound. [b] Yields are for the
isolated mixture of stereoisomers of the ozonides separated from the
residual diketone reactant by column chromatography on SiO . The ratio
2
1
of stereoisomers of the ozonides was determined from the H NMR
spectroscopic data.
2
,6-dione illustrate the importance of the Thorpe–Ingold
effect. We could obtain ozonides with a moderately bulky
substituent on the bridge (e.g., the Ph group in 2l) in up to
could be isolated by column chromatography and fully
characterized by NMR spectroscopy, mass spectrometry,
elemental analysis, and X-ray crystallography (Figure 4; see
the Supporting Information).
9
0% yield. Importantly, we could prepare ozonides with
pendant alkene and alkyne functionalities: compounds
impossible to obtain directly by the classical ozonolysis
route. Such groups should provide functional handles for
bioconjugation through click and other ligation techniques.
Interestingly, the transformation of 1,5-ketoaldehyde 1n into
ozonide 2n proceeded without oxidation of the aldehyde.
This process is readily scalable (gram quantities of the
starting diketones can be used) with only a small negative
effect on the yields of the ozonides. The reaction of H O with
2
2
3.0 g of diketone 1d provided the isolated mixture of
stereoisomeric ozonides 2d and 3d in 66% combined yield.
The synthesis of these new bicyclic ozonides gave us an
opportunity to explore the chemistry of this functionality. For
The reaction of H O2 with 2-substituted 1,5-diketones
2
created two new stereocenters and yielded a mixture of two
diastereomers. The resulting bicyclic ozonides were stable and
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3
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