Oxidative Ring Expansion of Cyclobutanols: Access to Functionalized 1,2-Dioxanes

Article abstract of DOI:10.1021/acs.orglett.1c00070

Cyclobutanols undergo an oxidative ring expansion with Co(acac)2 and triplet oxygen to give 1,2-dioxanols. The formation of an alkoxy radical drives the regioselective cleavage of the ring on the more substituted side before insertion of molecular oxygen. The reaction is particularly effective on secondary cyclobutanols but works also on certain tertiary alcohols. Further substitution with neutral nucleophiles under catalytic Lewis acid conditions led to original 1,2-dioxanes with a preferred 3,6-cis-configuration.

Full text of DOI:10.1021/acs.orglett.1c00070

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Letter
Oxidative Ring Expansion of Cyclobutanols: Access to
Functionalized 1,2-Dioxanes
̀
María Martín López, Nicolas Jamey, Alexis Pinet, Bruno Figadere, and Laurent Ferrié*
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ABSTRACT: Cyclobutanols undergo an oxidative ring expansion with Co(acac)2
and triplet oxygen to give 1,2-dioxanols. The formation of an alkoxy radical drives
the regioselective cleavage of the ring on the more substituted side before insertion
of molecular oxygen. The reaction is particularly effective on secondary
cyclobutanols but works also on certain tertiary alcohols. Further substitution with
neutral nucleophiles under catalytic Lewis acid conditions led to original 1,2-
dioxanes with a preferred 3,6-cis-configuration.
1,2-Dioxanes are a particular example of endoperoxides, which
can be found in many natural products. They are mainly
isolated from various sponges but also from other marine
species, plants, and fungi.1 Most of the natural dioxanes display
antiparasitic, antifungal, or cytotoxic activities. Although
hundreds of these natural substances were reported with
more or less variety in their structures, relatively few works
were driven toward their total synthesis.
improved by the use of milder catalysts, such as Sc(OTf)3 or
InCl3/TMSCl in a catalytic amount, which allows one to run
the reactions at room temperature with an expanded reagent
scope (Scheme 1).23
On the basis of this work, we were wondering if we could
apply this strategy to the synthesis of functionalized 1,2-
dioxanes. Indeed, Dussault earlier reported the nucleophilic
substitution on six-membered endoperoxyketal rings on 1,2-
dioxene derivatives in some pioneering studies.24 In contrast,
oxidative ring expansion of cyclobutanols under radical
conditions was relatively unknown, and there were concerns
that the difference of kinetics between cyclopropoxyl and
cyclobutoxyl radicals, by analogy with the cyclopropylmethyl
radicals25 and cyclobutylmethyl radicals,26 might not allow the
expected transformation in our favor. Nevertheless, a few
examples of ring opening of cyclobutyloxyl radicals were
reported in the literature, driving the formation of 1,4-
diketones under oxidative conditions27 or four-substituted
ketone derivatives when the radical is trapped with some good
radical acceptors.28 It is also important to note that during the
total synthesis of graciloether A the last key step included a
radical transformation of a particularly strained cyclobutane
ring into a 1,2-dioxane (Scheme 1).6
Many of these synthetic studies were targeting natural
products isolated from marine species and, more specifically,
marine sponges. Indeed, sponges are known to be a
tremendous pool for endoperoxides, and 1,2-dioxanes
represent a large part of them. Nevertheless, other natural
products with a 1,2-dioxane scaffold, produced by other marine
species, fungi, or plants, were studied for their total synthesis.
Indeed, synthetic works toward mycaperoxide B,2 9,10-
dihydroplakortin,3 peroxyplakoric acid A3,4 peroxyacarnoate
A&D,5 graciloether A,6 diacarnoxide C,7 plakortolide E,8,9
stolenoxides,10 and talaperoxides and other derivatives of the
chamigrane family,11 isoacetylsaturejone,12 yingzahosu
A
13,14&C,15,16 and steenkrotin B,17 were accomplished using
different strategies to build the key 1,2-dioxane ring (Figure
1).18
These past few years, our group was involved in a scientific
program toward the total synthesis of mycangimycin, a
polyunsaturated fatty acid containing an uncommon disub-
stituted 1,2-dioxolane ring.19 Our strategy was to build the
endoperoxide through an oxidative ring expansion of a
cyclopropanol to a 1,2-dioxolan-3-ol.20,21 We discovered that
the corresponding acetate can react with various silylated
nucleophiles through either Sakurai or Mukaiyama reactions,
catalyzed by strong Lewis acids such as TiCl4 or SnCl4 in
quasi-stoichiometric amounts.22 The process was further
To study the oxidative ring expansion of cyclobutanols into
1,2-dioxolan-3-ols, the desired starting materials were first
Received: January 8, 2021
Published: February 16, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00070
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1626−1631
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Scheme 2. Preparation of 2-Substituted Cyclobutanols 5a−f
a
and 6a−e
a
Final yields over four steps.
substrate was an excellent choice to start the study with, as a
driving force of the C−C bond cleavage would be the
stabilization of the new radical29 into the intermediate opened
product, and a benzene substituent could perfectly play this
role.
Figure 1. 1,2-Dioxane natural products involved in total synthesis
studies (in blue, isolated from sponges; in purple, from other marine
species, in green, from plants; in brown, from fungi).
By using reported conditions for the oxidative ring
expansion of cyclopropanols,20−23 it was observed that
cyclobutanol 5a did not react in the presence of Mn(acac)2
(Table 1, entries 1 and 2). Gratifyingly, Co(acac)2 proved to
Scheme 1. Oxidative Ring Expansion of Strained Cycloalkyl
Alcohols and Further Functionalization of the
Endoperoxyacetals
Table 1. Screening of Conditions for Oxidative Ring
Expansion of Cyclobutanol 5a into 1,2-Dioxane 7a
a
entry
metal salt
(mol %)
conditions
solvent
yield (%)
1
2
3
4
5
6
7
8
Mn(acac)2
Mn(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)3
1
5
1
5
5
5
100
5
rt, 48 h
rt, 48 h
rt, 24 h
rt, 48 h
rt, 48 h
40 °C, 8 h
rt
THF
THF
THF
THF
MeCN
MeCN
MeCN
MeCN
no reaction
no reaction
b
23
84
b
61
76
56
traces
b
prepared. For this purpose, we found that the most general
route was based on a Wittig olefination of ketones or aldehydes
1a−f with a cyclopropyl ylide. Further epoxidation with m-
CPBA provided unstable spiro-epoxycyclopropanes 3a−f,
which were converted into cyclobutanones 4a−f through a
pinacol rearrangement promoted by acid catalysis.29 On one
hand, further reduction with NaBH4 gave cyclobutanols 5a−f
as a mixture of diastereoisomers. Tertiary alcohols 6a−e were
also synthesized, on the other hand, by addition of an
organolithium or organomagnesium reagent onto cyclo-
butanones 4a−e (Scheme 2).
rt, 48 h
a
Isolated yield as a 60:40 mixture of diastereomers. Yield was
overestimated because of THF peroxide byproduct contamination.
promote strained cycle cleavage and be able to deliver a small
amount of desired product over 48 h (Table 1, entry 3).
Almost full conversion was attained with more cobalt salt
(Table 1, entry 4), but yield was overestimated because of a
large production of THF peroxide byproducts, which
contaminated the desired product. These side products were
not observed, in contrast, on the ring expansion of cyclo-
A first investigation of the oxidative ring expansion of
cyclobutanols was conducted on cyclobutanol 5a. This
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propanols because of the fast scission process. To overcome
this problem, we switched THF for MeCN, which seemed
inert to oxidation and allowed the transformation to occur,
providing dioxane 7a in 61% yield after 48 h at room
temperature (Table 1, entry 5). Increasing the temperature to
40 °C could decrease significantly the reaction time to 8 h,
improving the overall process (Table 1, entry 6). Using a
stoichiometric amount of cobalt(II) salt did not improve
significantly the kinetics of the reaction but lowered the yield
due to the appearance of some degradations (Table 1, entry 7).
Co(II) salt was essential to this reaction since starting directly
from a source of Co(III) proved to be unproductive (Table 1,
entry 8).
Scheme 3. Diverse Attempts Toward the Synthesis of 1,2-
Dioxan-6-ols 7b−g and 8a−e
Oxidative ring expansion was then applied to other
cyclobutanols 5b−f and 6a−e. Secondary alcohols 5b−f are,
in general, the best substrates for such a transformation.
Indeed, the reaction works well, with 2,2-disubstituted
cyclobutanols 5b−d and 5f, affording isolated yields above
60%. Monosubstituted cyclobutanol 7e was also able to
undergo an oxidative ring extension but required a longer
reaction time (up to 48 h). We also observed no reaction at
room temperature with this last substrate, so heating was
necessary in this case. Tertiary alcohols 6a−e were also
examined, and the first trials did not lead to good results.
Monosubstituted cyclobutanols 6a and 6e gave unsatisfactory
results: no conversion into dioxane 8e was observed from 6e.
Isolation of diketone 9a and hydroxyketone 10a in 36% and
24% yield, respectively, from cyclobutanol 6a was experienced
in place of dioxanol 8a. Isolation of these two unexpected
products means the reaction was probably working, but
compound 8a might undergo a Kornblum−DeLamare
rearrangement to form 9a, on one hand because the benzylic
position facilitates an elimination process. On the other hand,
hydroxyketone 10a might have been produced from 1,2-
dioxane 8a by homolytic cleavage of the peroxide bond, but
the exact pathway is currently unclear. In contrast, it was found
that 2,2-disubstituted cyclobutanols 5b−d and 5f were better
substrates for an oxidative ring expansion. However, the rate of
the reaction was slower compared to secondary alcohol
derivatives 6b−d, affording the desired products in lower
yields, sometimes with recovery of the unreacted starting
materials. This observation was unexpected and might be
attributed to steric hindrance for the formation of the
cyclobutyloxy radical rather than a decrease of the kinetics of
the radical scission (Scheme 3).
Although similar oxidation was reported in the literature, the
exact mechanism of how the peroxy radical species are formed
has never been determined.27 It seems plausible that
Co(II)(acac)2 is reacting with oxygen to form a
superoxocobalt(III) radical and a μ-peroxocobalt(III) spe-
cies.30 Indeed, the reaction mixture, in the presence of oxygen,
turns rapidly from a light brown color to intense green, which
is characteristic of Co(III) ions. Also, the inability of
Co(III)(acac)3 to promote the reaction (Table 1, entry 8)
indicates the crucial role of these oxocobalt(III) species.
Alkoxy radicals are less stable than peroxy radicals by about 4
kJ/mol31 and by consequence make hydrogen abstraction of a
hydroxyl group from A an endothermic process. However, the
strain ring scission which follows, with stabilization of the
radical at position 4, is highly exothermic, making the overall
process highly favorable [about −71 kJ/mol for scission of a
trans-2-methylcyclobutyloxyl radical (determined by calcula-
tion at the B3LYP/6-31+G(d,p)32 level of theory)]. Coordi-
nation of the hydroxyl group to the Co(III) species is also very
plausible during the hydrogen abstraction step, facilitated by a
directed process such as represented in B. Moreover, the
observed difficulty applying the reaction to tertiary cyclo-
butanols is consistent with higher steric hindrance of these
substrates, which strengthens the hypothesis of a coordination.
Regioselectivity in the carbon−carbon bond cleavage to C is
dependent on the ability of the new site to stabilize the new
radical species. Therefore, this driving force explains some
differences of reactivity between mono- and disubstituted
cyclobutanols. A molecule of 3O2 is then trapped by the
radical, making a new peroxyradical D, which can evolve
between the opened form E and the closed one F. One or the
other form might abstract a hydrogen atom from a new
cyclobutanol to propagate the reaction such as in path a, or a
cobalt(III) hydroperoxide species could reinitialize the process
from the beginning such as in path b (Scheme 4).
In order to prepare different 1,2-dioxanes, the so obtained
1,2-dioxanols 7a−g were then acylated using Yb(OTf)3 as a
Lewis acid catalyst to produce different acetate derivatives
11a−g.22,23 Further functionalization of these compounds was
initiated with different silylated nucleophiles. The catalytic
23
version of the nucleophilic substitution using Sc(OTf)3 was
chosen for this screening for better convenience. The reaction
of acetate 11e with allylTMS produced compound 12 as a sole
cis-product in 65% yield. In contrast, reaction of acetate 11e
with TMS cyanide was less selective and gave product 13 with
only a 65:35 cis:trans ratio,33 while Mukayama aldol reaction
with a ketene TMS-thioethylacetal furnished 1,2-dioxane 14
with a quite good diastereoselectivity. The synthesis of allyl
1,2-dioxane 15 from 11a was achieved in poor yield due to an
elimination process, which might take place more easily at the
benzylic position and produced many degradation products.22
Sakurai reactions on acetate 11b produced compounds 16 and
17 with pretty good yields. Mukaiyama reaction on acetate 11b
with silyl enol ether of acetophenone gave dioxane 18 in good
yield, and a vinylogous process was also possible to produce 19
from TMS-siloxyfuran as a 2:1 mixture of diastereomers.34
Reduction of acetal 11d with triethylsilane furnished
compound 20 in moderate yield. With unsymmetrical
dialkylated dioxanes 11c and 11d, the diastereoselectivity is
not as good as with monosubstituted compounds, but
generally a major isomer is observed such as in the synthesis
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reaction with a Lewis acid drives the formation of
peroxycarbenium species, which adopt a half-chair-like
conformation (Scheme 6).37 This species can evolve between
Scheme 4. Plausible Mechanism of the Cyclobutanol
Oxidative Ring Expansion
Scheme 6. Rationalization of the Observed Selectivity
Toward the 3,6-cis-Diastereoisomer in the Nucleophilic
Substitution of 1,2-Dioxanyl Acetates
conformations 27-eq and 27-ax, depending on if the
substituent is placed in an axial or equatorial position. Because
alkyl substituents prefer to adopt an equatorial position, the
major reactive conformer must be 27-eq. A nucleophilic
substitution then takes place preferentially to the axial position
of the peroxycarbenium species, which leads 27-eq to
compound 28-cis. In contrast, diastereoselectivity is poorer
from 6,6-disubstituted 1,2-dioxannyl acetates where no high
selective conformation of 27 could be adopted, except for 11c,
which gave decent selectivities due to the bulky t-butyl group
(75:25 and 85:15 selectivity for 23 and 24, respectively,
Scheme 5)
In conclusion, we developed new access to 1,2-dioxanes, by
using an original approach involving an oxidative ring
expansion of cyclobutanols under radical conditions.38 The
oxidation is regioselective, and its kinetics seem dependent on
the ability of the substituents to stabilize an intermediate alkyl
radical. The process seems to work particularly well with
secondary alcohols even if specific examples of tertiary alcohols
can also moderately work sometimes. Further functionalization
was then achieved. For instance, the corresponding acetates
11a−g, by generating reactive peroxycarbenium species, react
with neutral nucleophiles to afford the expected 1,2-dioxanes,
preferentially as the 3,6-cis-diastereoisomers. This new method
is able to provide quickly functionalized 1,2-dioxanes, which
would be difficult to prepare by another method. Indeed, this
approach would be very valuable for the synthesis of new
endoperoxides, but in particular for the total synthesis of
natural marine products containing a 1,2-dioxane moiety such
as mycaperoxides, stolonoxides, dihydroxyplakortides, diacarn-
oxide C, and many others, whose structures seem to
correspond to potential targets for its use.
of 1,2-dioxanes 21−24. Carbamate 7f proved to be unreactive
under our used Lewis acid catalysis, due to Lewis base
properties of the nitrogen function (Scheme 5).
The diastereoselectivity in this nucleophilic substitution
leads to the 3,6-cis-diastereomer as a major product, in an
analogous manner to 4-substituted tetrahydropyranyl ace-
tals.35,36 If we consider dioxanyl acetate 11e, for example,
Scheme 5. Functionalization of 1,2-Dioxanyl Acetates 11a−
g
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00070.
Experimental procedures, characterization data, Carte-
sian coordinates and energy diagram of a trans-2-
methylcyclobutoxyl radical, pentanal-4-yl radicals and
1629
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1
their transition state, and copies of H and 13C NMR
spectra of all compounds (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
Laurent Ferrié − BioCIS, CNRS, Université Paris-Saclay,
Châtenay-Malabry 92290, France; orcid.org/0000-0002-
1171-205X; Email: laurent.ferrie@universite-paris-saclay.fr
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Endoperoxide Family of Natural Products. Org. Lett. 2015, 17 (3),
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Authors
María Martín López − BioCIS, CNRS, Université Paris-
Saclay, Châtenay-Malabry 92290, France
Nicolas Jamey − BioCIS, CNRS, Université Paris-Saclay,
Châtenay-Malabry 92290, France
Alexis Pinet − BioCIS, CNRS, Université Paris-Saclay,
Châtenay-Malabry 92290, France
Bruno Figadere − BioCIS, CNRS, Université Paris-Saclay,
Châtenay-Malabry 92290, France; orcid.org/0000-
̀
(15) (a) Xu, X.-X.; Dong, H.-Q. Enantioselective Total Syntheses
and Stereochemical Studies of All Four Stereoisomers of Yingzhaosu
C. J. Org. Chem. 1995, 60 (10), 3039−3044. (b) Xu, X.-X.; Dong, H.-
Q. Enantioselective Total Synthesis of All Four Stereoisomers of
Yingzhaosu C. Tetrahedron Lett. 1994, 35 (50), 9429−9432.
(16) Boukouvalas, J.; Pouliot, R.; Fréchette, Y. Concise Synthesis of
Yingzhaosu C and Epi-Yingzhaosu C by Peroxyl Radical Cyclization.
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0003-4226-8489
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(17) Xuan, J.; Zhu, A.; Ma, B.; Ding, H. Diastereoselective Synthesis
of the Hydroperoxide−Keto Form of ( )-Steenkrotin B. Org. Lett.
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N. Jamey and A. Pinet thank the Ministere de l’Enseignement
Superieur, de la Recherche et de l’Innovation (MESRI), for a
PhD fellowship. M. Martín López thanks the European Union
for an Erasmus fellowship. We thank Nina Cooper (Université
Paris-Saclay) for exploratory studies, Karine Leblanc for
HRMS analysis (BioCIS, Chatenay-Malabry), and Jean-
Christophe Jullian (BioCIS, Chatenay-Malabry) for NMR
(18) Terent’ev, A. O.; Borisov, D. A.; Vil’, V. A.; Dembitsky, V. M.
Synthesis of Five- and Six-Membered Cyclic Organic Peroxides: Key
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