Reaction of peroxyacetals with silyl ketene acetals: Synthesis of 3- peroxyalkanoates and 3-peroxyalkanals

Article abstract of DOI:10.1016/S0040-4039(00)00914-X

Lewis acid-mediated reaction of monoperoxyacetals with silyl ketene acetals (SKAs) provides an efficient approach to 3-peroxyalkanoates. Propionate SKAs react with aliphatic peroxyacetals to furnish 3-peroxy-2- methyl alkanoates with modest anti-selectivity. Although acetate and thioacetate SKAs are less reactive, the latter react with unsaturated peroxyacetals to furnish peroxyalkenoates and -alkadienoates which undergo chemoselective reduction to 3-peroxyalkenals and 3-peroxyalkadienals. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00914-X

Tetrahedron Letters 41 (2000) 5457±5460
Reaction of peroxyacetals with silyl ketene acetals: synthesis
of 3-peroxyalkanoates and 3-peroxyalkanals
P. H. Dussault,* R. J. Lee, J. A. Schultz and Y. S. Suh
Department of Chemistry, University of Nebraska±Lincoln, Lincoln, NE 68588-0304, USA
Received 24 April 2000; revised 30 May 2000; accepted 1 June 2000
Abstract
Lewis acid-mediated reaction of monoperoxyacetals with silyl ketene acetals (SKAs) provides an ecient
approach to 3-peroxyalkanoates. Propionate SKAs react with aliphatic peroxyacetals to furnish 3-peroxy-
2-methyl alkanoates with modest anti-selectivity. Although acetate and thioacetate SKAs are less reactive,
the latter react with unsaturated peroxyacetals to furnish peroxyalkenoates and -alkadienoates which
undergo chemoselective reduction to 3-peroxyalkenals and 3-peroxyalkadienals. # 2000 Elsevier Science
Ltd. All rights reserved.
Peroxyalkanoates are common substructures in cyclic peroxide natural products, as well as
potentially useful synthetic intermediates.1 However, methodology for synthesis of this motif
remains limited.2,3 In contrast, 3-alkoxyalkanoates are readily available via reaction of silyl
ketene acetals (SKAs) and acetals.4 We recently reported a new approach to peroxide synthesis
based upon Lewis acid-mediated reactions of peroxyacetals with allylsilanes and silyl enol
ethers.5,6 We now report the synthesis of 3-peroxyalkanoates through corresponding reactions of
peroxyacetals with SKAs (Fig. 1). In addition, we demonstrate the chemoselective conversion of
peroxyalkanoates to peroxyalkanals.
Figure 1. Lewis acid-mediated addition to peroxyacetals
Aliphatic (1a,1b) and benzylic (2a,2b) peroxyacetals were prepared through ozonolysis of
alkenes or enol ethers in methanol or 2-methoxyethanol, followed by silylation of the resulting
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00914-X

5458
hydroperoxyacetals (Scheme 1).7 10 Peroxyacetal 3 was obtained from 13-hydroperoxyocta-
decadienoic acid using a reported procedure.11 Synthesis of allyl peroxyacetal 4 was achieved
through tetra-per¯uoropropylporphyrin (TPFPP)-sensitized photooxygenation12,13 of an enol
ether,14 followed by silylation of the hydroperoxyacetal.9 The diene peroxyacetal 5, prepared
similarly from a dienol ether,15 decomposed exothermically upon chromatography and was used
without puri®cation.
Scheme 1. Peroxyacetal substrates: (a) hexylMgBr, CuBr; (b) TPFPP, O2, hn, CCl4; (c) TBSCl, Imid.; (d) HC(OMe)3,
TsOH; (e) TMSOTf, i-Pr2NEt
Reactions of aliphatic peroxyacetal 1a with the SKAs of ethyl acetate or ethyl thioacetate failed
to produce the peroxyalkanoate. The corresponding reaction with the SKA of benzyl acetate,
although occasionally successful, was not consistently reproducible. In contrast, reaction with
(E)- or (Z)-propionate SKAs16 reproducibly furnished 3-peroxy-2-methyl alkanoates 7 as a mixture
of easily distinguished (1H) diastereomers. Reaction of the propionate SKAs with the benzylic
peroxyacetals 2a and 2b proceeded in higher yield but without diastereoselection (Table 1).
Table 1
Synthesis of 3-peroxy-2-methylalkanoates

5459
The relative stereochemical con®guration of the 3-peroxy-2-methylheptanoates 7 was assigned
following deprotection and reduction to furnish a 70:30 mixture of anti and syn-3-hydroxy-2-
methylalkanoates 9 (Fig. 2).17 Interestingly, deprotection with n-Bu4NF resulted in isolation of 8
and 9 as a 50:50 mixture of syn- and anti-diastereomers. The ability to achieve epimerization
without decomposition, a potentially useful approach to syn-peroxypropionates, is surprising
given the intermediacy of 3-peroxyenolates in nucleophilic epoxidations.18
Figure 2. Stereochemical correlation
Alkoxydioxine 3 failed to react with acetate, thioacetate, or propionate SKAs, instead under-
going slow decomposition. The formation of allylated dioxane11 upon addition of allytrimethyl-
silane veri®ed the presence of a reactive intermediate, suggesting the lack of reaction with the
more nucleophilic SKAs19 may simply be due to decomposition under the prolonged reaction
conditions (Fig. 3).
Figure 3. Attempted synthesis of dioxine acetates and propionates
Allyl acetal 4 reacted with the SKAs of benzyl acetate, t-butylthioacetate, and ethyl thioacetate
to furnish 3-peroxyalkenoates. The labile diene peroxyacetal 5 reacted with the trimethylsilyl SKA
of ethyl thioacetate to produce the peroxyalkadienoate thioester (Fig. 4). The peroxyalkenoates
and -alkadienoates were stable, easily puri®ed, compounds.
Figure 4. Synthesis of peroxyalkenoates
Chemoselective reduction of the 3-peroxyalkenoate and 3-peroxyalkadienoate thioesters was
investigated as a possible approach to synthetic precursors of hydroperoxyeicosatetraenoic acids
(HPETEs). For both the allyl and dienyl series, low temperature DIBAL reduction proceeded in
moderate to good yield to produce stable 3-peroxyaldehydes (Fig. 5).

5460
Figure 5. Synthesis of peroxyalkenals
In conclusion, reaction of silyl ketene acetals with peroxyacetals provides an ecient approach
to 3-peroxyalkanoates and 3-peroxyalkanals. Investigation of asymmetric versions of this trans-
formation and applications to the total synthesis of peroxide natural products are in progress.
Acknowledgements
We are grateful to the NIH for support and to Professor Richard Shoemaker for assistance
with NMR experiments.
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^20ꢀC is added TMSOTf (0.1 mmol). The completed reaction (TLC) is quenched by rapid addition of EtOAc (10
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1
Rf=0.53 in 10% EA/hexane; H NMR 4.23 (m, 1H), 4.10 (m, 2H), 3.08 (qd, 1H, J=7.16, 5.60), 1.08 (d, 3H,
J=7.16), 1.40±0.80 (18H), 0.8 (s, 6H). Anal. calcd for C15H34O4Si: C, 60.33; H, 10.76. Found: C, 60.24; H, 10.74.
1
Ethylthio (4E)-3-(1,1-dimethylethyldimethylsilyldioxy)-4-undecenoate: Rf=0.6 (10% EtOAc/hexanes); H NMR
(300 MHz) 5.73 (dt, 1H, J=15.2, 6.7), 5.35 (ddt, 1H, J=15.5, 7.8, 1.4), 4.71 (q, 1H, J=6.7), 3.08 (dd, 1H, J=14.5,
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18.1, 14.1, ^5.7; IR (neat): 1698 cm^1; HRMS (FAB) calcd for C19H38O3SSi (M+Li)+: 381.2327. Found: 381.2471.
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