Isotetronic acids from an oxidative cyclization

Article abstract of DOI:10.1039/c5cc04051e

Oxidation of α,β-unsaturated methyl ketones with selenium dioxide leads to a cascade of reactions culminating in the formation of isotetronic acids.

Full text of DOI:10.1039/c5cc04051e

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DOI: 10.1039/C5CC04051E
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Isotetronic Acids from an Oxidative Cyclization
Z. Zhou,a P. M. Wallesera and M. A. Tiusa,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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Abstract. Oxidation of α,β-unsaturated methyl ketones with Herein we report a synthesis of this chemotype that makes use of a
selenium dioxide leads to a cascade of reactions culminating in the different strategy. We had observed that α-ketoacid 1 was stable in
formation of isotetronic acids.
CH3
OH
spontaneous
H3C
Ph
O
(1)
O
Isotetronic acids (2-hydroxybutenolides) are a common structural
motif in natural products derived from marine and terrestrial fungi,
bacteria, marine algae and plants. For example, butyrolactone I was
isolated in 1977 from cultures of Aspergillus terreus var. africans1
whereas retipolide E is the putative biosynthetic precursor2,3 of a
number of structurally related isotetronic acids isolated from the
fruiting bodies of North American Retiboletus sp. fungi.
CO2H
O
Ph
1
2
solution over several days at room temperature, but underwent
spontaneous cyclization to isotetronic acid 2 upon removal of the
solvent (Eq 1). We postulated that under the appropriate conditions
methyl enones that are very simple to prepare would undergo
oxidative cyclization to isotetronic acids. After screening conditions,
we determined that exposure of enones to a modest excess of
selenium dioxide in pyridine resulted in a reaction cascade
culminating in the formation of the isotetronates in moderate or
good yield as illustrated in Eq 2.8 Methyl enone 3 that was prepared
in 63% yield by means of piperidine catalyzed aldol condensation9
was heated in pyridine solution with selenium dioxide in a re-
sealable sealed tube. Workup led to isotetronic acid 4 in 67% yield
following chromatographic purification. The reaction presumably
takes place through the initial oxidation of the methyl group in 3 to
the carboxylate that undergoes cyclization spontaneously under the
reaction conditions.
OH
HO
OH
O
HO
O
OH
O
OH
O
CO2Me
O
O
retipolide E
butyrolactone I
O
Useful pharmacological activities are sometimes associated with
this substructure, for example butyrolactone I is a potent inhibitor
of CDK1 and CDK2, both of which play a key role in mammalian cell
cycle progression, and it has consequently been of interest as a lead
for cancer chemotherapeutic drug development.4,5 This has
generated considerable interest in the synthesis of this type of
structure that has most often been prepared through aldol addition
OCH3
H3CO
2.2 eq SeO2
pyr, sealed tube
110 oC, 5 min;
90 oC 16 h
OH
F
4
O
of
a α-ketoester to an aldehyde followed by spontaneous
(2)
O
5
lactonization.6 The α-ketoesters are typically not commercially
available. Langer and coworkers developed a distinct approach to 4-
alkoxycarbonyl isotetronates whereby oxalyl chloride was
condensed with 1,3-bis(trimethylsilyloxy)alk-1-enes.7 In both
approaches the isotetronic acid was disconnected into fragments of
the appropriate oxidation state.
O
67% yield
3
4
CH3
F
The scope of the reaction is illustrated in Table 1. The reaction
succeeds in the case of electron-rich or electron-poor aryl groups at
C4 or C5 (4 – 9). An ester group at C4 is well tolerated (10 – 13).
Note that allylic oxidation of the ester group apparently does not
represent an appreciable side reaction (13). C4 benzoyl
isotetronates 14 and 15 both formed in good yield. Compounds 5
and 6 have been mentioned in the literature,10 as have 10, 11,7 1411
and 15.12
We were curious to learn what would be the reaction outcome for
substrates that offered a second site at which oxidation could take
place, so the two tetrasubstituted alkenes 16a and 16b were
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subjected to the reaction conditions using 2.2 equiv of selenium respectively, as the major reaction products in modest yield (Eqs 4,
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dioxide (Eq 3). 3-Carboethoxyfurans 17a13 and 17b14 were formed 5). These products may have been formed from oxidation of the
DOI: 10.1039/C5CC04051E
as the major products in modest yield, indicating that oxidation of allylic methylene group to the alcohol, followed by oxidation of the
the allylic methylene group to the alcohol in each case took place methyl group to the acid, double bond isomerization and
faster than oxidation of the acetyl methyl group.
cyclization. The modest yields of the pyrones should be weighed
against the ease of their synthesis and the speed with which these
complex structures can be prepared from very simple starting
materials.
Table 1. Examples of the oxidative cyclization
H3CO
H3CO
H3CO
Tertiary benzylic alcohol 22 was converted in 13% yield to 5-
hydroxypyrone 24 as the major product (Eq 6). The difference in the
outcome of this reaction and the reactions of Eqs 4 and 5 can be
understood by considering that elimination of the alcohol under the
reaction conditions presumably led to styrene 23 as the initial
product. The C1 methyl group that is activated subsequently
underwent oxidation to the carboxylate. Oxidation of the C4
methylene group to the ketone, followed by partial oxidation of the
C5 methyl group and cyclization leads to the observed product. In a
separate experiment, 22 was converted to 23 by exposure to
methanesulfonyl chloride and Hünig’s base in 64% yield. Exposure
of 23 to selenium dioxide in pyridine in a second step led to 24 in
30% yield, or in 19% overall yield from 22.
OH
OH
OH
O
O
O
O
O
O
5
55%
6
61%
4
67%
H3CO
F3C
F
H3CO
OH
OH
OH
F3C
O
O
O
O
O
O
7
75%
8
56%
O
9
73%
F
O
O
O
OH
OH
OH
EtO
EtO
EtO
O
O
O
TBSO
TBSO
TBSO
1
Me
Me
O
O
O
(6)
O
12
10
60%
11
66%
OH
Me
63%
F
H3CO
O
4
22
23
24
Me
HO
O
O
O
In summary, a convenient oxidative cyclization of methyl enones
leads to isotetronic acids (Eq 2). Substrates with oxidizable allylic
methylene or methyl groups lead either to furans (Eq 3), or to
pyrones (Eqs 4-6). These results demonstrate a means through
which simple molecules undergo a rapid increase in molecular
OH
OH
OH
O
O
O
O
O
O
O
O
O
13
58%
14
73%
15
70%
H3CO
F
Plausible mechanisms of the oxidative cyclization leading to the complexity and suggest many opportunities for discovery.
isotetronic acids are either an intramolecular oxa-Michael addition As a historical footnote, during the execution of this work we
of the carboxylate carbonyl oxygen atom of the transiently formed became aware of only one oxidative cyclization related to ours. In
α-ketoacid with simultaneous proton transfer from the carboxylate 1898 during the course of his structural elucidation of the ionones,
to the enol, or perhaps an oxa-Nazarov 4 π conrotation of the same Tiemann reported that oxidation of ionone with potassium
α-ketoacid.15
permanganate led to a compound melting at 130 oC that he named
“oxyjonolacton” and to which he assigned structure 27.16 In
subsequent years β-lactone 28 was described as Tiemann’s
“hydroxyionolactone”.17,18 In 1961 Brooks and coworkers,
prompted by the implausibility of the structure 28, repeated
Tiemann’s work and suggested that α-ketoacid 25 was one of the
oxidation products formed from permanganate oxidation of β-
ionone and that 26 (and not 28) was the correct structure of
“oxyjonolacton”.19 Brooks and coworkers made their structural
assignment on the basis of infrared and ultraviolet spectroscopy
O
O
O
CH3
O
EtO
(3)
EtO
CH3
R1
R1
R2
R2
16a R1 = Me, R2 = H
16b R1, R2 = (CH2)4
17a R1 = Me, R2 = H, 31%
17b R1, R2 = (CH2)4, 36%
O
O
O
OH
O
(4)
CH3
49% yield
O
O
O
Me
OH
18
19
Me
O
O
Me
H3C
CH3
OH
KMnO4
OH
Me
O
H3CO
H3CO
Me
Me
Me
Me
β-ionone
Me
Me
O
O
25
26
CH3
(5)
O
Me
Me
HO
O
38% yield
O
Me
20
21
H3C
CH3
H3C
CH3
O
OH
Me
Me
The oxidative cyclization of trisubstituted alkenes 18 and 20 took a
different course and led to 3-hydroxypyrones 19 and 21,
O
Me
27
28
Scheme 1. Tiemann’s reaction
2 | J. Name., 2012, 00, 1-3
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13 A. O. Chagarovsky, E. M. Budynina, O. A. Ivanova, E. V.
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Villemson, V. B. Rybakov, I. V. Trushkov and M. Y. Melnikov,
DOI: 10.1039/C5CC04051E
and also the elemental analysis that suggested the correct
molecular formula for 26.20 Moreover, the melting point of Brooks’
26 (129 – 131 oC) closely matched the one recorded by Tiemann for
“oxyjonolacton”. In 2007 Kamat and coworkers revisited Tiemann’s
and Brooks’ work and with the benefit of X-ray crystallography,
NMR and mass spectrometry were able to unambiguously show
that 26 is indeed the correct structure of hydroxyionolactone.21 This
all leaves little doubt that Tiemann’s reaction and ours are the same
and allows us to trace the origins of our work to the late 19th
century.
Org. Lett., 2014, 16, 2830–2833.
14 E. J. Corey and A. K. Ghosh, Chem. Lett., 1987, 223–226.
15 The intramolecular oxa-Michael addition is a forbidden 5-
endo-trig process and may therefore be less likely than the
oxa-Nazarov mechanism. See S.I. and Scheme 1 in: J. E.
Baldwin, J. Cutting, W. Dupont, L. Kruse, L. Silberman and R.
C. Thomas, Chem. Commun., 1976, 736–738.
16 F. Tiemann, Chem. Ber., 1898, 31, 808–866. The procedure
for the oxidation and structure 27 appear on p. 857. This
oxidation was apparently performed on the mixture of α-
and β-ionones since the separation of the two ionone
isomers is first mentioned in his next paper that immediately
follows: F. Tiemann, Chem. Ber., 1898, 31, 867–881.
17 (a) Simonsen, J. L. “The Terpenes”, Cambridge University
Press, 2nd ed., 1947, Vol. I, p. 128. (b) E. H. Rodd, “Chemistry
of Carbon Compounds”, Elsevier, Amsterdam, 1953, Vol. II, p.
503.
Notes and references
18 To the best of our knowledge, Tiemann never showed a β-
lactone structure for his “oxyjonolacton”, so the origin of 28
remains unclear. Note also that 27 might have been an
expected product of permanganate oxidation of α-ionone,
whereas it is an unlikely oxidation product of β-ionone.
Tiemann may have contributed to some of the confusion in
Chem. Ber. 1898, 31, 867–881 by showing the correct
structure of α-ionone, but labelling it as β-ionone on p. 870,
then showing the same structure on p. 874 labelled as α-
ionone. On p. 881 he showed the correct structure for β-
ionone but labelled it as α-ionone. On pp. 872–873 the
oxidation of β-ionone to “oxyjonolacton” with
permanganate is mentioned and structure 27 shown,
referring to his preceding paper for the procedure. In a paper
published posthumously, Tiemann correctly assigned
structures to α- and β-ionone: F. Tiemann, Chem. Ber., 1900,
33, 3703–3710.; see pp. 3709–3710.
19 C. J. W. Brooks, G. Eglinton and D. S. Magrill, J. Chem. Soc.,
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20 It is interesting to note that Tiemann’s elemental analytical
data more closely matched the correct C/H ratio for 26 than
for 27, the structure he assigned.
21 S. P. Kamat, A. M. D’Souza, S. K. Paknikar, M. M. Bhadbhade
and R. G. Gonnade, Ind. J. Chem., 2007, 46B, 1038–1041.
Note that there is an error in the structure shown for 26
(compound 3 in the paper) on the first page: the angular
methyl group is missing. The correct structure appears later
in the paper.
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