Synthesis and reactivity of 1,2-dioxolanes from β,γ-epoxy ketones

Article abstract of DOI:10.1021/ol500835f

Five-membered ring peroxides were prepared in one step in 31-86% yield from readily accessible β,γ-epoxy ketones and H₂O₂. The reaction proceeded via a tetrahydrofuran, which was converted to the thermodynamically favored 1,2-dioxola

Full text of DOI:10.1021/ol500835f

Letter
pubs.acs.org/OrgLett
Synthesis and Reactivity of 1,2-Dioxolanes from β,γ-Epoxy Ketones
Wynne V. Kandur, Kathleen J. Richert, Curtis J. Rieder, Andrew M. Thomas,‡ Chunhua Hu,
Joseph W. Ziller,§ and K. A. Woerpel*
Department of Chemistry, New York University, 100 Washington Square East, New York, New York 10003, United States
S
* Supporting Information
ABSTRACT: Five-membered ring peroxides were prepared in one step in 31−86% yield from readily accessible β,γ-epoxy
ketones and H2O2. The reaction proceeded via a tetrahydrofuran, which was converted to the thermodynamically favored 1,2-
dioxolane. The product contains a leaving group, which can be displaced to synthesize analogues of the plakinic acid natural
products.
eroxide-containing natural products, including nardosi-
Scheme 1. Synthesis of a 1,2-Dioxolane
P
none,1 the monoterpene isolated from Adenosma caeruleum
(1),2 epiplakinic acid C,3 and epiplakinic acid E methyl ester4
(Figure 1), represent a family of biologically active compounds
β,γ-epoxy ketones, can be synthesized in three steps from an
aldehyde, requiring purification of only the final products (eq 2).
The synthesis of 1,2-dioxolanes was general for several epoxy
ketones (Table 1). The reaction conditions were optimized for
each epoxy ketone to form dioxolanes 3a−g in the highest yield
with the lowest catalyst loading. The reactions of alkyl and
Figure 1. Peroxide-containing natural products.
Table 1. Synthesis of 1,2-Dioxolanes
that are difficult to isolate and synthesize.5 Among methods used
to prepare the 1,2-dioxolane core of these natural products,
approaches using oxygen and ozone as the source of oxygen
atoms have been effective.6,7 In contrast, the use of H2O2 has
been less successful. Acid- or base-mediated addition of H2O2
into diketones or α,β-unsaturated ketones gave dioxolanes in low
yields,8,9 with limited substrate scope,10−16 or gave the 1,2-
dioxolane as one component of a mixture.17−19 In this Letter, we
demonstrate that 1,2-dioxolanes can be prepared in one step
using H2O2 and that the products can be functionalized to
provide structural analogues of the plakinic acids.
Our synthesis of 1,2-dioxolanes involves connecting two
electrophilic groups, an epoxide and a carbonyl group, with H2O2
to form the endoperoxide ring in one step.20 For example, the
addition of H2O2 to β,γ-epoxy ketone 2a catalyzed by
phosphomolybdic acid (PMA)21,22 or phosphotungstic acid
(PTA)23 provided 1,2-dioxolane 3a in 86% yield (eq 1, Scheme
1). This one-flask synthesis of dioxolanes avoided the handling of
unstable hydroperoxyketal intermediates.24 The synthesis of 1,2-
dioxolanes is operationally simple because the starting materials,
a
R
time (h)
product
yield (%)
dr
c
(CH2)2Ph
CH2Ph
21
72
8
3a
3b
3c
3d
3e
3f
86
71:29
75:25
71:29
67:33
57:43
67:33
75:25
d
54
e
(CH2)4CH3
81
b
c
(CH2)2OX
25
2
58
f
Ph
41
c
4-CF3-Ph
4-Me-Ph
22
4
33
c
3g
31
a
1
dr = trans-3/cis-3, as determined by H NMR spectroscopic analysis
b
c
of the unpurified reaction mixture. X = TBDPS. Isolated yield using
catalytic PMA (2 mol %). Using catalytic PTA (50 mol %). Using
catalytic PTA (20 mol %). Using catalytic PTA (10 mol %).
d
e
f
Received: March 19, 2014
Published: April 29, 2014
© 2014 American Chemical Society
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Letter
benzylic ketones (3a−d) gave products in higher yield than
reactions of aromatic ketones (3e−g). The reaction rate was
slower when the carbonyl group was near an electron-
withdrawing substituent (3b, 3d, and 3f), suggesting that a
reactive intermediate developed a positive charge at the carbonyl
carbon atom (vide infra). The dioxolanes could be formed using
other catalysts such as Re2O7, Mo(IV)O2, a complex of
Na2MoO4 with glycine, and phosphoric acid,20,25−27 but the
reactions were slower.
membered rings, the four relevant C−O bonds are generally
shorter than typical C−O bond lengths (1.43 Å for ethers, 1.45 Å
for peroxides).32,33 For example, the short endocyclic C−O bond
of tetrahydrofuran 6 (1.40 Å) and the short C−OO bonds of
dioxolane 3f (1.42 Å) suggest that donation of electrons from
oxygen atoms into σ*C−OO bonds occurs (Figure 3). The σ*C−OO
Optimizing the 1,2-dioxolane synthesis required careful
structural analysis because the dioxolane is the thermodynamic
product, not the kinetic product. At short reaction times (1 h), a
spectroscopically similar product, tetrahydrofuran 5, was formed,
but longer reaction times led to the formation of the desired
dioxolane 3 (Figure 2). In the initial stages of optimization, it was
Figure 3. Differences in selected C−O bond lengths.
orbital should be a good electron acceptor: it is likely lower in
energy than σ*C−O because the second oxygen atom would
withdraw electron density34,35 from the proximal oxygen atom.
In contrast, the longer C−OO bond of tetrahydrofuran 6 (1.44
Å) compared to the shorter ones in the dioxolane 3f (1.42 Å)
indicates that the exocyclic oxygen atom of the peroxide group is
likely donating little electron density into the endocyclic σ*C−O
of tetrahydrofuran 6.36 This diminished donation from the
peroxide oxygen atom is likely due to the large difference in
energy between the nonbonding orbitals of the peroxide oxygen
atom and σ*C−O of the tetrahydrofuran.37,38 As a result, the
tetrahydrofuran has one strong hyperconjugation interaction,
whereas the 1,2-dioxolane has two such interactions and is thus
more stabilized. These trends hold for other crystal structures in
this series, and they mirror observations in the literature.28,39,40
The tetrahydrofuran 5b is an exception to this pattern of bond
lengths, but it is also an exception in its reactivity: it is the slowest
of the compounds to isomerize to the thermodynamic product
(Table 1).
Figure 2. 13C NMR chemical shifts of products.
difficult to assign these structures, but with several kinetic and
thermodynamic products in hand, it became possible to assign
their structures based on the slight differences in their 1H and 13C
NMR spectra. In the tetrahydrofuran 5, the methylene group
bearing an oxygen atom exhibited chemical shifts that were
downfield by about δ 7 ppm in the 13C NMR spectra and δ 0.6−
0.8 ppm in the 1H NMR spectra compared to the corresponding
dioxolane 3 (Figure 2).28 Because these chemical shift differences
alone are insufficient to assign structures unambiguously, we
obtained X-ray crystal structures of several tetrahydrofurans (5b
and 6) and dioxolanes (3a,b,e−g) to confirm the structural
assignments.
A mechanism that incorporates the above observations is
outlined in Scheme 4. The addition of H2O2 to the more
Further insight into the mechanism of 1,2-dioxolane formation
emerged during optimization studies. When Sc(OTf)3 was used
as the catalyst with aqueous H2O2 and acetonitrile, acetamide 6
was formed (Scheme 2). This product resembles the
Scheme 4. Mechanism of Peroxide Addition
Scheme 2. Participating Solvent
substituted carbon atom of the protonated epoxide22,41 would
lead to ketone 8, drawn complexed to a Lewis or Brønsted acid.
In acetonitrile (Scheme 2), ring opening of the epoxide by
solvent would be favored, leading to amide 6.29 The carbonyl
carbon atom of ketone 8 could be attacked by either the hydroxyl
group (path a) or the hydroperoxyl group (path b, Scheme 4).
Because the hydroxyl group is a harder nucleophile,42 it should
add more rapidly to the activated carbonyl group. Upon longer
exposure to the acidic conditions, the thermodynamically
favored dioxolane 3 could form. In aqueous H2O2 (Scheme 3),
the peroxyketal 3 could undergo hydrolysis, leading to peroxide
7a.
In the course of manipulating the 1,2-dioxolane products, it
was discovered that triethylamine reduced the peroxyketal to
form hemiperketal 7a and 7d (Scheme 5).43 This transformation
led to products resembling the biologically active monoterpenoid
peroxide 1 (Figure 1). Other amines, such as DBU, DABCO, i-
Pr2NEt, and pyridine, accomplished this reduction, but the
reactions were slower. The reduction by triethylamine is a milder
tetrahydrofuran product 5 (Figure 2), except that a molecule
of acetonitrile was incorporated instead of one of the equivalents
of H2O2.29 Bi(OTf)3 also catalyzed the addition of aqueous
30
H2O2 to epoxy ketone 2a, but the product incorporated only 1
equiv of H2O2, forming hemiperketal 7a (Scheme 3).
X-ray crystallographic data suggested a reason why the 1,2-
dioxolane is thermodynamically favored. The kinetic and
thermodynamic products exhibit general differences in C−O
bond lengths, suggesting that hyperconjugation stabilizes the
dioxolane more than the tetrahydrofuran.31 In both types of five-
Scheme 3. Synthesis of a Hemiperketal
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Organic Letters
Letter
however. Oxidation of the unpurified aldehyde 14a to the
corresponding carboxylic acid 15a also resulted in a product that
was unstable to purification. The acid, however, could be
converted to ester 16a, which was stable to chromatography.
Manipulations of the unprotected allylated dioxolane 9a were
more successful. Oxidation of the major stereoisomer of alkene
9a gave aldehyde trans-17a, and the minor stereoisomer formed
the lactol 18a, which could be removed by chromatography
(Scheme 9). The aldehyde trans-17a was converted in 72% yield
to ester trans-16a (Scheme 9), whose structure resembles that of
the plakinic acids (Figure 1).
Scheme 5. Reduction of Dioxolanes to Hemiperketals
alternative to the use of more forcing conditions, such as Zn/
HOAc or Mg/MeOH, which reduce both endo- and exocyclic
peroxide bonds.44 The reduction by triethylamine appears to be
selective because hydroperoxides bearing electron-withdrawing
groups are reduced more rapidly than alkyl hydroperoxides,43,45
which are likely to be intermediates during the stereochemical
isomerization at the acetal carbon atom (Scheme 5).
Scheme 9. Functionalization of Unprotected Dioxolane 9a
Transformations of the dioxolanes 3 demonstrate their utility
for preparing analogues of the plakinic acids.7 The exocyclic
hydroperoxyl group of dioxolane 3a can serve as a leaving group
for nucleophilic substitution reactions (Scheme 6).8,46 With the
Scheme 6. Allylation of Dioxolane 3a
Another difficult structural assignment emerged upon
exploring these oxidations. The lactol 18a obtained from the
minor stereoisomer of dioxolane 9a was oxidized to form lactone
cis-19a (Scheme 10). Similarly, oxidation of tetrahydrofuran cis-
pendent nucleophilic oxygen atom (O3) unprotected, rearrange-
ment to tetrahydrofuran cis-10a occurred, presumably through
intramolecular attack onto the peroxycarbenium ion 11a
(Scheme 7). This hypothesis was confirmed by observing that
Scheme 10. Oxidation to Lactones
Scheme 7. Rearrangement to Tetrahydrofuran 10a
allylation of a protected version of dioxolane 3a gave the
protected allyl compound 13a free of any rearrangement product
(Scheme 8).
10a, the minor product formed upon allylation of trans-3a
(Scheme 6), led to peroxylactone cis-20a (Scheme 10). Lactone
cis-19a and peroxylactone cis-20a shared similar carbonyl
stretching frequencies (1736 and 1740 cm−1, respectively) and
13C NMR chemical shifts for the carbonyl carbon atom (δ 171.9
and 170.1 ppm, respectively).47 Differences in two-dimensional
NMR spectra (particularly HMBC and COSY) assisted in
assigning the structures.28 Eventually, X-ray crystallography
confirmed the structure of lactone cis-19a, which permitted the
structural assignment of the peroxylactone cis-20a.
Scheme 8. Functionalization of Protected Dioxolane 13a
In conclusion, we have demonstrated a new method to form
1,2-dioxolanes in a single step using acid-catalyzed addition of
H2O2 to β,γ-epoxy ketones. The resulting dioxolanes possess
functional groups that enable elaboration, leading to the
synthesis of plakinic acid analogues.15 Because the enantiose-
lective epoxidation of homoallylic alcohols can be used to
prepare enantiopure β,γ-epoxy ketones,48 this method should
lead to the synthesis of homochiral 1,2-dioxolanes.
Oxidation of the allyl group of protected 1,2-dioxolanes
allowed for the synthesis of analogues of the plakinic acids
(Scheme 8), but this sequence proceeded with low yields.
Dioxolane 13a, which was obtained by acylating dioxolane 9a,
was oxidized to aldehyde 14a, which was unstable to
chromatography. This reaction afforded recovered allylated
dioxolane 13a as the major product (13a:14a = 67:33). Attempts
to increase the conversion of the oxidation led to decomposition,
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kwoerpel@nyu.edu.
Present Addresses
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‡Chevron Oronite LLC, Richmond Technology Center,
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§Department of Chemistry, University of California, Irvine, CA
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Science Foundation
(CHE-0848121) and is based on work supported by the National
Science Foundation Graduate Research Fellowship under Grant
No. DGE-1342536 to support K.J.R. We thank Dr. Chin Lin
(NYU) for assistance with NMR spectroscopy and mass
spectrometry, and Dr. John Greaves (UCI) and Ms. Shirin
Sorooshian (UCI) for mass spectrometric data. We also thank
the Molecular Design Institute of NYU for purchasing a single-
crystal diffractometer.
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