Synthesis of silyl monoperoxyketals by regioselective cobalt-catalyzed peroxidation of silyl enol ethers: Application to the synthesis of 1,2-dioxolanes

Article abstract of DOI:10.1021/ol5020015

The cobalt-catalyzed peroxidation of silyl enol ethers with molecular oxygen and triethylsilane provided silyl monoperoxyketals in 54%-96% yield. These compounds serve as precursors to peroxycarbenium ions, which undergo annulations to provide 1,2-dioxola

Full text of DOI:10.1021/ol5020015

Letter
pubs.acs.org/OrgLett
Synthesis of Silyl Monoperoxyketals by Regioselective Cobalt-
Catalyzed Peroxidation of Silyl Enol Ethers: Application to the
Synthesis of 1,2-Dioxolanes
Brisa Hurlocker, Matthew R. Miner, and K. A. Woerpel*
Department of Chemistry, New York University, New York, New York 10003, United States
S
* Supporting Information
ABSTRACT: The cobalt-catalyzed peroxidation of silyl enol
ethers with molecular oxygen and triethylsilane provided silyl
monoperoxyketals in 54%−96% yield. These compounds serve
as precursors to peroxycarbenium ions, which undergo
annulations to provide 1,2-dioxolanes.
a
he five-membered ring cyclic peroxide motif is found in
Scheme 1. Formation of a Peroxycarbenium Ion
T
biologically active natural and synthetic products such as
epiplakinic acid E methyl ester, plakortide E, and Arterolane
(OZ277).1,2 These peroxides (Figure 1) possess a range of
a
R3 = H, TBS; R4 = Me, Et, octyl, CH2CH2OMe; Lewis acid = SnCl4,
TiCl4, Me3SiOTf, or phosphomolybdic acid.
In this Letter, we report a method to prepare a new
peroxycarbenium ion precursor using molecular oxygen as the
source of oxygen atoms (Scheme 2). The cobalt-catalyzed
Scheme 2. Silyl Monoperoxyketal Synthesis
Figure 1. Biologically active five-membered ring peroxides.
peroxidation of silyl enol ethers also protects the peroxide
functionality directly, minimizing the need to handle unstable
hydroperoxy compounds. Compared to the use of bisperoxy-
ketals (such as 2), this method contains only the oxygen−
oxygen bond required for synthesis of the peroxide functional
group in the product. These substrates also have the advantage
that only substoichiometric quantities of Lewis acid are needed
to generate the peroxycarbenium ion intermediate required for
annulation reactions leading to 1,2-dioxolanes.
The method reported here extends the utility of the cobalt-
catalyzed peroxidation of alkenes,24 a powerful method for the
synthesis of peroxides. The addition of molecular oxygen and
triethylsilane to alkenes forms silylated peroxides with
unfunctionalized alkenes25−28 and 1,2-dioxanes and 1,2-
dioxolanes with dienes.29 Application of this reaction to alkenes
biological properties such as antimalarial,3,4 antifungal,5 and
cytotoxic activity.6 Although the development of new cyclic
peroxides for applications as pharmaceutical agents would be
valuable, the synthesis of these motifs remains challenging
because of the weak oxygen−oxygen bond7 and the dangers
associated with peroxide formation.
Among the methods developed for the synthesis of exo- and
endocyclic peroxides,8−11 annulations of peroxycarbenium ions
with alkenes have proven to be useful for the construction of
peroxides such as 1,2-dioxolanes.12−18 Peroxycarbenium ions
are most commonly generated from either bisperoxyketals3,14,19
such as 2 or alkoxyperoxyketals20 such as 3 and an amount of
Lewis acid (Scheme 1). The synthesis of monoperoxyketals as
peroxycarbenium ion precursors20,21 typically requires ozone22
or excess hydrogen peroxide23 as the source of oxygen atoms.
Additional steps to protect the hydroperoxide functionality are
often necessary to provide bench-stable compounds.19,20
Received: July 9, 2014
Published: August 1, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
with heteroatom substituents, however, has not been explored.
On the basis of previous mechanistic investigations,30 we
hypothesized that peroxidation of silyl enol ethers would
proceed via a stabilized alkoxy-substituted radical intermedi-
ate31 7, which would allow for the synthesis of silyl
monoperoxyketal intermediates such as 6 (Scheme 3).
Scheme 3. Formation of a Stabilized Radical
Figure 2. Structures of CoII catalysts.
these enol ethers were prepared in one step by enolization of
the ketone with a lithium amide base followed by the addition
of triethylsilyl chloride. Some substrates required no further
purification, but if purification was necessary, column
chromatography over silica gel or distillation provided analyti-
cally pure products.
The peroxidation of silyl enol ethers is general for a range of
substrates (Table 2). Aromatic silyl enol ethers with electron-
withdrawing groups reacted to form products in the highest
yields (entries 2 and 3), while reactions of silyl enol ethers with
electron-donating groups resulted in lower yields (entry 1) or
more decomposition (entry 5). Electron-withdrawing groups
likely stabilize the radical intermediate 7, giving a greater yield
of the peroxide and presumably stabilizing the silyl monoper-
oxyketal products by disfavoring their decomposition by mild
acids such as silica gel. Cyclic compounds 30 and 32 gave the
corresponding peroxides in similar yields in a 1:1 diastereo-
meric ratio (entries 11 and 12). It was not important that the
enolization step be regio- or stereoselective, because each
component of the mixture of silyl enol ethers led to the same
product (entries 6, 9, and 10).
The cobalt-catalyzed peroxidation reaction with oxygen and
triethylsilane was an effective method for the synthesis of silyl
monoperoxyketals. Treatment of trimethylsilyl enol ether 8a
under standard conditions24 (20 mol % Co(acac)2, 1 atm of O2,
and 2 equiv of Et3SiH) gave the desired silyl monoperoxyketal
9a in 38% yield after 12 h (Table 1, entry 1). The remainder of
Table 1. Optimization of Reaction Conditions
ab
,
entry
R
catalyst
solvent
yield (%)
1
2
3
4
5
6
7
8
Me
Et
Et
Et
Et
Et
Et
Et
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(modp)2
Co(modp)2
Co(thd)2
ClCH2CH2Cl
ClCH2CH2Cl
MeCN
38
54
57
25
48
22
68
PhCF3
MeCN
PhCF3
To probe the effectiveness of the silyl monoperoxyketal
functional group as a peroxycarbenium ion precursor, a [3 + 2]
annulation reaction with silyl monoperoxyketal 9b and 1,1-
disubstituted alkene 34 was attempted (Scheme 4). A variety of
MeCN
e
c
Co(thd)2
PhCF3
80
a
b
The main byproduct was acetophenone. The reaction was complete
c
d
in 12 h. The reaction was complete in 1 h. 8,9a, R = Me; 8,9b, R =
Et. 10 mol % Co(thd)2.
e
Scheme 4. [3 + 2] Annulation of Silyl Monoperoxyketal
the starting material decomposed to acetophenone. Reaction of
the more stable triethylsilyl32 enol ether 8b led to fewer
decomposition products in the unpurified reaction mixture,
leading to easier purification and a higher yield of the desired
product (54%, entry 2).
The peroxidation of silyl enol ethers was optimized by
changing the catalyst and solvent. A limited selection of
solvents that have the propensity to dissolve oxygen were
chosen for screening.33 Slightly higher yields could be obtained
using acetonitrile as the solvent in place of 1,2-dichloroethane.
Lewis acids were screened in stoichiometric and substoichio-
metric amounts, including BF3·OEt2, AlCl3, TiCl4, HfCl4,
SnBr4, Et3SiCl, and Bu3SnCl. All Lewis acids were found to give
unreacted starting material or acetophenone as the final
product. The use of 5 mol % SnCl4, however, provided the
1,2-dioxolane 35 in 51% yield. The use of larger quantities of
SnCl4 provided no increase in yield.
The selective ionization of the silyloxy group by a strong
Lewis acid is consistent with previous studies on the ionization
of mixed acetals.35 Complexation of a strong Lewis acid to the
more basic silyloxy group is favored, leading to ionization of
that group (complex 36, Figure 3). Association of a Lewis acid
to form complex 37 is disfavored due to the electron-
withdrawing silyloxy group, which causes the complexing
oxygen atom to become less basic.36
24
Use of the catalysts Co(modp)2 (bis(1-morpholino-
carbamoyl-4,4-dimethyl-1,3-pentanedione)cobalt(II)) and Co-
34
(thd)2 (bis(2,2,6,6-tetramethylheptane-3,5-dione)cobalt(II))
(Figure 2) was effective in delivering the desired product
(entries 5 and 7). Changing the solvent from acetonitrile to
trifluorotoluene with Co(thd)2 afforded the desired product 9b
in 80% yield in a shorter time (1 h, entry 8). Analysis of the
unpurified reaction mixture obtained under these conditions
showed that the product was clean enough to use in the
subsequent reactions without purification.
A range of aromatic and aliphatic silyl enol ethers were
prepared from commercially available ketones to test the
generality of the peroxidation reaction (Table 2). In most cases,
The purity of SnCl4 has a significant influence on the
effectiveness of the silyl monoperoxyketal 9b as a peroxycarbe-
nium ion precursor. The reaction of silyl monoperoxyketal 9b
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Organic Letters
Letter
Table 2. Silyl Monoperoxyketal Synthesis
Figure 3. Possible ionization pathways of silyl monoperoxyketals.
and alkene 34 with stoichiometric or trace ethereal HCl gave
only acetophenone with no formation of annulation product
35. This result indicates that even small quantities of HCl in
solutions of Lewis acid are detrimental to the reaction.37
To demonstrate the utility of the [3 + 2] annulation, a range
of 1,2-dioxolanes were synthesized from silyl monoperoxyketals
and nucleophilic alkenes (Table 3). The reaction of silyl
monoperoxyketal 31 with alkene 38 gave the cyclic peroxide
39, which resembles the core of synthetic 1,2-dioxolane 1
Table 3. 1,2-Dioxolane Synthesis
a
b
a
b
c
1
Isolated yield. The silyl monoperoxyketal 19 was observed by H
Isolated yield. The product was formed as a single diastereomer. In
NMR spectroscopy, but it was unstable to chromatography on silica
gel. Isolated as a 1:1 mixture of diastereomers.
situ deprotection with n-Bu4NF gave the alcohol in 53% yield.
Isolated as an 87:13 mixture of diastereomers.
c
d
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Organic Letters
Letter
Scorneaux, B.; Tang, Y.; Urwyler, H.; Wittlin, S.; Charman, W. N.
Nature 2004, 430, 900.
(5) Chen, Y.; McCarthy, P. J.; Harmody, D. K.; Schimoler-O’Rourke,
R.; Chilson, K.; Selitrennikoff, C.; Pomponi, S. A.; Wright, A. E. J. Nat.
Prod. 2002, 65, 1509.
(6) Horton, P. A.; Longley, R. E.; Kelly-Borges, M.; McConnell, O. J.
J. Nat. Prod. 1994, 57, 1374.
(7) Bach, R. D.; Ayala, P. Y.; Schlegel, H. B. J. Am. Chem. Soc. 1996,
118, 12758.
(8) Terent’ev, A. O.; Borisov, D. A.; Vil’, V. A.; Dembitsky, V. M.
Beilstein J. Org. Chem. 2014, 10, 34.
(Figure 1). The protected hydroxyl group of 39 allows for
further functionalization to either the carboxylic acid or ester
moiety present in many natural products.16,19 The annulation
of ethyl-substituted silyl monoperoxyketal 29 using diethyl-
substituted alkene 34 afforded cyclic peroxide 44, which
resembles the ethyl-substituted core of plakortide E (Figure 1).
Installation of long alkyl chains present in many 1,2-dioxolane
natural products can be achieved, as shown by the synthesis of
cyclic peroxide 45. The diastereoselectivity observed in
annulation product 43 can be ascribed to a synclinal transition
state, analogous to the annulation of allylic silanes with
aldehydes.38 The synthesis of 1,2-dioxolane 42 demonstrates
the advantage of silyl monoperoxyketals as peroxycarbenium
ion precursors, because previous syntheses have required up to
10 equiv of Lewis acid to effect the transformation.19,39
In conclusion, the cobalt-catalyzed peroxidation of silyl enol
ethers using molecular oxygen and triethylsilane provides an
efficient method for the synthesis of silyl monoperoxyketals.
The reaction is general for aryl- and alkyl-substituted silyl enol
ethers, and the enol ether can be embedded in a five- or six-
membered ring. These silyl monoperoxyketals also serve as
effective peroxycarbenium ion precursors, requiring only
substoichiometric amounts of Lewis acid for their formation.
This development allows for the rapid synthesis of the 1,2-
dioxolane core found in many natural products.
(9) McCullough, K. J.; Nojima, M. Curr. Org. Chem. 2001, 5, 601.
(10) Tian, X.-Y.; Han, J.-W.; Zhao, Q.; Wong, H. N. C. Org. Biomol.
Chem. 2014, 12, 3686.
(11) Sun, X.-Y.; Tian, X.-Y.; Li, Z.-W.; Peng, X.-S.; Wong, H. N. C.
Chem.Eur. J. 2011, 17, 5874.
(12) Dussault, P. H.; Liu, X. Org. Lett. 1999, 1, 1391.
(13) Dussault, P. H.; Lee, H.-J.; Niu, Q. J. J. Org. Chem. 1995, 60,
784.
(14) Martyn, D. C.; Ramirez, A. P.; Beattie, M. J.; Cortese, J. F.; Patel,
V.; Rush, M. A.; Woerpel, K. A.; Clardy, J. Bioorg. Med. Chem. Lett.
2008, 18, 6521.
(15) Dussault, P. H.; Lee, I. Q. J. Am. Chem. Soc. 1993, 115, 6458.
(16) Kandur, W. V.; Richert, K. J.; Rieder, C. J.; Thomas, A. M.; Hu,
C.; Ziller, J. W.; Woerpel, K. A. Org. Lett. 2014, 16, 2650.
(17) Li, Y.; Wittlin, S.; Wu, Y. Heterocycles 2012, 86, 245.
(18) Wang, X.; Dong, Y.; Wittlin, S.; Creek, D.; Chollet, J.; Charman,
S. A.; Santo Tomas, J.; Scheurer, C.; Snyder, C.; Vennerstrom, J. L. J.
Med. Chem. 2007, 50, 5840.
ASSOCIATED CONTENT
(19) Ramirez, A.; Woerpel, K. A. Org. Lett. 2005, 7, 4617.
(20) Dussault, P. H.; Lee, I. Q.; Lee, H.-J.; Lee, R. J.; Niu, Q. J.;
Schultz, J. A.; Zope, U. R. J. Org. Chem. 2000, 65, 8407.
■
S
* Supporting Information
Experimental procedures, characterization, and spectral data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
̌
(21) Zmitek, K.; Zupan, M.; Iskra, J. Org. Biomol. Chem. 2007, 5,
3895.
(22) Dussault, P. H.; Davies, D. R. Tetrahedron Lett. 1996, 37, 463.
̌
(23) Zmitek, K.; Zupan, M.; Stavber, S.; Iskra, J. J. Org. Chem. 2007,
72, 6534.
AUTHOR INFORMATION
■
(24) Isayama, S. Bull. Chem. Soc. Jpn. 1990, 63, 1305.
(25) Silva, E. M. P.; Pye, R. J.; Cardin, C.; Harwood, L. M. Synlett
2010, 509.
(26) Barnych, B.; Fenet, B.; Vatel
(27) Barnych, B.; Vatele, J.-M. Org. Lett. 2012, 14, 564.
Corresponding Author
*E-mail: kwoerpel@nyu.edu
Notes
̀
e, J.-M. Tetrahedron 2013, 69, 334.
̀
(28) O’Neill, P. M.; Pugh, M.; Davies, J.; Ward, S. A.; Park, B. K.
Tetrahedron Lett. 2001, 42, 4569.
The authors declare no competing financial interest.
(29) Tokuyasu, T.; Kunikawa, S.; McCullough, K. J.; Masuyama, A.;
Nojima, M. J. Org. Chem. 2005, 70, 251.
(30) Tokuyasu, T.; Kunikawa, S.; Masuyama, A.; Nojima, M. Org.
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 B.H.
M.R.M. acknowledges a Margaret Strauss Kramer Fellowship
from the NYU Department of Chemistry. The Bruker Avance-
400 MHz spectrometer was acquired through the support of
the National Science Foundation (CHE-01162222). We thank
Dr. Chin Lin (NYU) for assistance with NMR spectroscopy
and mass spectrometry. We thank Amy Y. Chan (NYU Girls’
Science, Technology, Engineering, and Mathematics Summer
Program) for technical assistance.
Lett. 2002, 4, 3595.
(31) Hioe, J.; Zipse, H. In Encyclopedia of Radicals in Chemistry,
Biology and Materials; Chatgilialoglu, C., Studer, A., Eds.; Wiley:
Hoboken, NJ, 2012; Vol. 1, pp 449−476.
(32) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031.
(33) Battino, R.; Rettich, T. R.; Tominaga, T. J. Phys. Chem. Ref. Data
1983, 12, 163.
(34) O’Neill, P. M.; Hindley, S.; Pugh, M. D.; Davies, J.; Bray, P. G.;
Park, B. K.; Kapu, D. S.; Ward, S. A.; Stocks, P. A. Tetrahedron Lett.
2003, 44, 8135. This complex is also known as Co(dpm)2 (ref 24).
(35) Maeda, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 1997, 62,
6429.
(36) Shambayati, S.; Blake, J. F.; Wierschke, S. G.; Jorgensen, W. L.;
Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 697.
REFERENCES
(1) Casteel, D. A. Nat. Prod. Rep. 1999, 16, 55.
■
(37) Solutions of SnCl4 purchased from two different suppliers
catalyzed the annulation reaction comparably. Control experiments in
which the reaction mixture was doped with 5 and 10 mol % ethereal
HCl provided no annulation products.
(38) Smitrovich, J. H.; Woerpel, K. A. Synthesis 2002, 2778.
(39) Dussault, P. H.; Zope, U. Tetrahedron Lett. 1995, 36, 3655.
(2) Liu, D.-Z.; Liu, J.-K. Nat. Prod. Bioprospect. 2013, 3, 161.
(3) Martyn, D. C.; Beletsky, G.; Cortese, J. F.; Tyndall, E.; Liu, H.;
Fitzgerald, M. M.; O’Shea, T. J.; Liang, B.; Clardy, J. Bioorg. Med.
Chem. Lett. 2009, 19, 5657.
(4) Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman, S. A.;
Chiu, F. C. K.; Chollet, J.; Dong, Y.; Dorn, A.; Hunziker, D.; Matile,
H.; McIntosh, K.; Padmanilayam, M.; Santo Tomas, J.; Scheurer, C.;
4283
dx.doi.org/10.1021/ol5020015 | Org. Lett. 2014, 16, 4280−4283