Synthesis of 1,2-dioxolanes by annulation reactions of peroxycarbenium ions with alkenes

Article abstract of DOI:10.1021/ol051703u

(Chemical Equation Presented) The annulation reactions of alkenes with peroxycarbenium ions enable the synthesis of a variety of functionalizable 1,2-dioxolanes. Triethysilyl-protected peroxycarbenium ions proved to be optimal for the annulation reaction. Using this method, plakinic acid analogues can be synthesized in three steps from the corresponding ketone and alkene.

Full text of DOI:10.1021/ol051703u

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4617-4620
Synthesis of 1,2-Dioxolanes by
Annulation Reactions of
Peroxycarbenium Ions with Alkenes
Armando Ramirez and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine, California 92697-2025
kwoerpel@uci.edu
Received July 19, 2005
ABSTRACT
The annulation reactions of alkenes with peroxycarbenium ions enable the synthesis of a variety of functionalizable 1,2-dioxolanes. Triethysilyl-
protected peroxycarbenium ions proved to be optimal for the annulation reaction. Using this method, plakinic acid analogues can be synthesized
in three steps from the corresponding ketone and alkene.
The peroxide moiety is present in over 200 marine and
terrestrial natural products, many of which possess potent
biological activity.1-8 For example, plakinic acid E and four
of its isomers have been isolated from Plakortis sp., and they
are cytotoxic against a range of cancer cell lines (Figure 1).9
introduce the peroxide moiety, current methodology relies
on reactions of ozone, singlet oxygen, and radical transfor-
mations involving molecular oxygen.13-20
Peroxycarbenium ions have emerged as useful reactive
intermediates for the synthesis of peroxides.21-25 For ex-
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Figure 1. Natural products.
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10.1021/ol051703u CCC: $30.25
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ample, Dussault and Zope reported that reactions of per-
oxycarbenium ions 1 with allyltrimethylsilane provide 1,2-
dioxolanes (Figure 2).26 In this paper, we demonstrate an
larger the silyl group, the greater the stability of the
peroxyketal, but the increased size resulted in lower product
yields. In general, the smaller the silyl group, the better the
annulation yield. Protection with the triethylsilyl group was
found to be optimal for peroxycarbenium ion generation and
trapping.30 In this case, cyclic peroxide 10 was obtained in
80% yield as a single diastereomer,31 arising from equatorial
attack to the peroxycarbenium ion intermediate.32
The utility of silyl peroxyketals was expanded by synthe-
sizing several substrates from the corresponding ketones
(Table 2). Attempting to synthesize peroxyketals according
Figure 2. Synthesis of cyclic peroxides.
Table 2. Synthesis of Silyl Peroxyketals
efficient generation of peroxycarbenium ions and their
reactions with alkenes that permit the rapid synthesis of
plakinic acid analogues.
We considered that some of the difficulties in the genera-
tion and reactivity of peroxycarbenium ions centered on the
terminal oxygen atom. The success of the reaction shown in
Figure 2 requires the terminal oxygen to be protected, but
upon reaching intermediate 2, the oxygen must be nucleo-
philic. Angle, in the course of developing annulations for
the synthesis of tetrahydrofurans and tetrahydropyrans,
encountered a similar challenge. He satisfied these require-
ments by protection of hydroxy aldehydes as their silyl
ethers.27-29
The use of silyl-protected peroxyketals provided an ideal
balance between stability and reactivity. Various peroxyketals
were investigated in the annulation reaction with 1,1-
disubstituted alkene 4 (Table 1). No annulation products were
Table 1. Investigation of Silyl Protecting Groups in
Peroxycarbenium Ion Formation
a Typical reaction conditions: (1) HCO2H (30 equiv), H2O2 (30 equiv,
50 wt % in H2O), 25 °C, 10 min; (2) Et3SiCl or Et3SiOTf (2.5-4.5 equiv),
Et3N (2.5-4.5 equiv), 0-25 °C, 4-18 h. b Typical reaction conditions:
(1) CF3CO2H (12 equiv), H2O2 (9 equiv, 50 wt % in H2O), 25 °C, 5 min;
(2) Et3SiOTf (3.2 equiv), Et3N (3.0 equiv), 25 °C, 16 h. c Yields based on
purified products.
to literature procedures resulted primarily in the formation
of dimers and trimers.33-36 The formation of oligomers was
(27) Angle, S. R.; El-Said, N. A. J. Am. Chem. Soc. 1999, 121, 10211-
10212.
(28) Angle, S. R.; El-Said, N. A. J. Am. Chem. Soc. 2002, 124, 3608-
3613.
a Typical reaction conditions: SnCl4 (2.0 equiv) and olefin (3.0 equiv)
in CH2Cl2, -78 to -3 °C, 4-24 h. b Yields based on purified products.
1
c Determined by H NMR spectroscopy.
(29) Angle, S. R.; Belanger, D. S.; El-Said, N. A. J. Org. Chem. 2002,
67, 7699-7705.
(30) Our results are consistent with the relative rate of hydrolysis of silyl
protecting groups: Schelhaas, M.; Waldmann, H. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2056-2083.
(31) The stereochemistry was proven by X-ray crystallographic analysis
of a colorless crystal of 1,2-dioxolanol 40.
obtained with unprotected peroxyketal 5. Silyl-protected
peroxyketals, however, engaged in annulation reactions. The
(22) Dussault, P. H.; Lee, H.-J.; Niu, Q. J. J. Org. Chem. 1995, 60, 784-
785.
(32) Laemmle, J.; Ashby, E. C.; Roling, P. V. J. Org. Chem. 1973, 38,
2526-2534.
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Lett. 2000, 41, 5457-5460.
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K. J.; Kim, H.-S.; Shibata, Y.; Wataya, Y. Tetrahedron Lett. 1999, 40,
4077-4080.
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J. A.; Zope, U. R. J. Org. Chem. 2000, 65, 8407-8414.
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Cullough, K. J.; Kim, H.-S.; Wataya, Y. Tetrahedron Lett. 2000, 41, 4681-
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4618
Org. Lett., Vol. 7, No. 21, 2005

minimized using chlorinated solvents and strongly acidic
conditions. Treatment of ketone 11 under the optimized
reaction conditions followed by silyl protection resulted in
74% yield of the stable and easily handled silyl peroxyketal
7, requiring only one purification.
Table 4. Alkene Scope: Investigating the Effect of Alkene
Nucleophilicity
The success of the annulation reaction is sensitive to the
structure of the silyl peroxyketal (Table 3). Cyclohexanone-
Table 3. Synthesis of 1,2-Dioxolanes from Silyl Peroxyketals:
Substrate Scope
a Typical reaction conditions: SnCl4 (2.0 equiv), alkene (3.0 equiv), -78
to -3 °C, 3-24 h. b Typical reaction conditions: SnCl4 (10 equiv), alkene
(4.0 equiv), -78 to +25 °C, 24 h. c Typical reaction conditions: SnCl4
(1.0 equiv), alkene (3.0 equiv), -78 to -5 °C, 22 h. d Stereochemistry
determined by analysis of DPFGSE-NOE data. e Yields based on purified
products.
a Typical reaction conditions: SnCl4 (2.0 equiv) and alkene (3.0 equiv)
in CH2Cl2, -78 to -3 °C, 2-4.5 h. b Determined by 1H NMR spectroscopy.
c Yields based on purified products.
tuted alkenes as nucleophiles. Allylsilanes, which are com-
parably nucleophilic to 1,1-disubstituted alkenes,43 also serve
as potent nucleophiles to trap peroxycarbenium ions. Al-
though p-methylstyrene 35 is as nucleophilic as allyltri-
methylsilane,43 an annulation using this alkene provided 1,2-
dioxolane 36 and polymeric material.
A variety of monocyclic peroxides can be obtained
employing silyl peroxyketal 19 (Table 5). Entry 1 shows the
ideal system for establishing not only the cyclic peroxide
moiety but also installating the acetic acid side chain common
to peroxide natural products (vide infra).1,2
derived structures are favorable for the annulation reaction
(entries 1 and 2). Annulation of silyl peroxyketal 19 provided
1,2-dioxolane 21, which posseses the core structure of the
Plakortis natural products (entry 3).9 Entries 4 and 5 represent
examples in which the driving force for Baeyer-Villiger
oxidation37-42 is greater than that of annulation, even under
optimized conditions.
Various alkenes can be employed as nucleophiles in the
annulation reaction with silyl peroxyketal 7 (Table 4).
Optimum results were obtained by employing 1,1-disubsti-
The use of a readily oxidized silyl group for the annulation
reaction allowed us to obtain synthetically useful peroxides.
Silyl groups can require forcing conditions to be oxidized,44-46
but the labile benzhydryldimethylsilyl group proved to be
useful for the synthesis of 1,2-dioxolanols.47 Under relatively
(35) Hamann, H. J.; Liebscher, J. J. Org. Chem. 2000, 65, 1873-1876.
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Org. Lett., Vol. 7, No. 21, 2005
4619

required to introduce the acetic acid side chain common to
many peroxide natual products (Scheme 2).1,2 Dioxolanes
Table 5. Synthesis of Monocyclic 1,2-Dioxolanes
Scheme 2
27 and 37, prepared in one step from the corresponding silyl
peroxyketals, were converted to structures resembling the
plakinic acids by oxidation of the primary alcohol.48 Sub-
sequent methylation of the carboxylic acid afforded 1,2-
dioxolane methyl carboxylates 42 and 43 in good yield.49
In conclusion, the annulation reactions of alkenes with
peroxycarbenium ions enables the synthesis of a variety of
functionalizable 1,2-dioxolanes. The silyl protecting group
used in the generation of peroxycarbenium ions governs the
success of the annulation reaction. With the appropriate
choice of ketones and alkenes, plakinic acid analogues can
be synthesized in three steps.
a Typical reaction conditions: SnCl4 (1.0-2.0 equiv), alkene (1.0-3.0
equiv), -78 to -3 °C, 2-3 h. b Determined by 1H NMR spectroscopy.
c Yields based on purified products. d Measured by HPLC analysis of the
unpurified reaction mixture. e The major diastereomer was isolated, and its
stereochemistry was determined by analysis of DPFGSE-NOE data.
mild conditions, oxidation of the carbon-silicon bond
occurred without significant destruction of the peroxide
linkage (Scheme 1).
Acknowledgment. This research was supported by the
National Institute of General Medical Sciences of the
National Institutes of Health (GM61006) and the National
Science Foundation (CHE-0135572). K.A.W. thanks Amgen,
Johnson & Johnson, and Merck Research Laboratories for
awards to support research. We thank Dr. Joseph Ziller for
X-ray crystallographic data, Dr. Phil Dennison for assistance
with NMR spectrometry, and Dr. John Greaves and Dr. John
Mudd for mass spectrometry.
Scheme 1
Supporting Information Available: Complete experi-
mental procedures and product characterization. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL051703U
(48) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936-3938.
(49) Yuan, P.; Plourde, R.; Shoemaker, M. R.; Moore, C. L.; Hansen,
D. E. J. Org. Chem. 1995, 60, 5360-5364.
The reactions of peroxycarbenium ions with protected
butenol 26 allows for the rapid synthesis of plakinic acid
analogues. This alkene incorporates all of the carbons
4620
Org. Lett., Vol. 7, No. 21, 2005