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Fragmentation of β-Hydroxy Hydroperoxides Xiaodong Gu,† Wujuan Zhang,‡ and Robert G. Salomon* Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States S Supporting Information *
ABSTRACT: A β-hydroxy hydroperoxide was obtained through basecatalyzed disproportionation of a hydroperoxy endoperoxide available by singlet oxygenation of cyclohepta-1,4-diene. Vitamins E and C induce fragmentation of this β-hydroxy hydroperoxide generating aldehydes, especially in the presence of redox active metal ions such as those present in vivo, e.g., under conditions of “iron overload”. This chemistry may contribute to the oxidative cleavage of polyunsaturated fatty acyls that produces similar aldehydes, which damage proteins and DNA through covalent adduction resulting in “oxidative injury”.
O
We chose the hydroperoxy endoperoxide 1 (Scheme 2) as a simple model system that would deliver a single product 3 by
xidative cleavage of unsaturated fatty acyls produces aldehydes in vivo. Many of these aldehydes are toxic, causing “oxidative injury” owing to damage of proteins or DNA through covalent adduction. We postulated that β-hydroxy hydroperoxides (Scheme 1c) are one type of intermediate that
Scheme 2
Scheme 1
fragmentation of an intermediate β-hydroxy hydroperoxide 2. Notably, the electrophilic conjugated enedione functionality present in 3 is also found in certain, especially toxic, lipid oxidative fragmentation products, e.g., 4-oxo-2-nonenal, that damage proteins21 and DNA22 through covalent adduction. The hydroperoxy endoperoxide 1 is readily available through singlet oxygenation of cyclohepta-1,4-diene.3 Reaction conditions were defined that optimized the conversion of 1 into 2, an analogue of the PUFA-derived γ-hydroxyalkenone of Scheme 1. This model β-hydroxy hydroperoxide was exploited to define reaction conditions that promote fragmentation. Disproportionation of the endoperoxide 1 was expected to produce β- and γ-hydroxyhydroperoxides 2 and 5 (Scheme 3). However, attempted use of triethylamine to catalyze23 the isomerization of endoperoxide 1 delivered a ketodiol 4 and a cyclic hydroxydione hemiacetal 7, in isolated yields of 50 and 14%, respectively, and none of the desired β-hydroxy hydroperoxide 2. The production of 7 undoubtedly involves dehydration of the α-hydroperoxy ketone array in 5. Reduction of 2 by triethylamine presumably accounts for the generation of 4. It is known that amines can reduce hydroperoxides to alcohols.24 For example, tert-butyl hydroperoxide was reduced by tri-n-propylamine to give alcohol in good yield (∼ 80%) and products generated through fragmentation of tripropylamine,
may be susceptible to fragmentation under mild physiological conditions. Possible routes to β-hydroxy hydroperoxides include Kornblum−DeLaMare rearrangement1 of β-hydroperoxy alkylperoxides (Scheme 1a,b). Singlet oxygenation of conjugated hydroperoxy dienes generates the requisite endoperoxides (Scheme 1a).2,3 Hydroperoxy dienes, which are major4 products of both enzymatic and free radicalpromoted oxidation of polyunsaturated fatty acyls (PUFAs), accumulate in atherosclerotic lesions.5 Singlet oxygen can be generated in vivo through photosensitization6 by retinal7 in the eye as well as nonphotochemically.8−10 β-Hydroperoxy alkylperoxides (Scheme 1b) are also produced by free radical cyclization of unsaturated peroxy radicals11−13 formed during the autoxidation of PUFAs.14,15 β-Hydroxy hydroperoxides (Scheme 1c) are also available through addition of H2O2 to epoxides (Scheme 1d)16−18 or through singlet oxygenation of allylic alcohols (Scheme 1e).19,20 © 2011 American Chemical Society
Received: September 26, 2011 Published: December 28, 2011 1554
dx.doi.org/10.1021/jo201910g | J. Org. Chem. 2012, 77, 1554−1559
The Journal of Organic Chemistry
Note
Scheme 3
Scheme 5
oxime derivative 12,29 which is stable and whose structure was further confirmed by mass spectroscopy. Thus, the structures of cis- and trans-aldehydes 3 and 10 were unambiguously confirmed. Previous studies showed that β-hydroxy hydroperoxides are subject to acid-16,17 or base-catalyzed18,30 fragmentation to carbonyl compounds. We examined the ability of amine bases or carboxylic acids (Table 1) to catalyze the fragmentation of 2
which included di-n-propylamine (32%) and carbonyl compounds (mainly 2-methyl-2-pentenal, 17%). Other bases were also tested as catalysts for disproportionation. Proton sponge (N,N,N′,N′-tetramethyl-naphthalene-1,8diamine), DABCO (1,4-diaza-bicyclo-[2.2.2]-octane), or pyridine were added to solutions of 1 in CDCl3, and the reactions were monitored by NMR. Endoperoxide 1 is stable in the presence of pyridine. The main product generated through catalysis by proton sponge or DABCO is 7 (Scheme 3). In an alternative route to 2 (Scheme 4), hydroperoxy endoperoxide 1 was first protected by treatment with 2-
Table 1. Acid and Base Promoted Decomposition of 2 unreacted (%)
Scheme 4
catalyst (in CH2Cl2)
reaction time
pyridine Et3N CF3COOH
12 h 5h 12 h
2
30
product yields (%) 3
10
4
38
16 57
1
Scheme 6
methoxypropene to give 8.25 In contrast with 1, triethylaminecatalyzed isomerization of the methoxyisopropyl derivative 8 of hydroperoxide 1 delivered 9 in 58% yield together with 7 in 13% yield. Deprotection of 9 under mild acidic conditions delivered the requisite β-hydroxy hydroperoxide 2 in 70% yield. Acetic acid was used to catalyze the deprotection of 9 in a mixed solvent system of hexafluoro-2-propanol and methylene chloride. The isolation of 2 was facilitated by the ease with which acetic acid can be removed by rotary evaporation into a dry ice-cooled trap under high vacuum. This simple route provided ready access to the β-hydroxy hydroperoxide 2 for the proposed fragmentation reaction studies. The contrasting behavior of the hydroperoxide 1 and 2-methoxypropyl derivative 8 is especially striking. It provides a useful protection strategy. The discovery that such derivatives are not reduced by amines, in contrast with the hydroperoxide precursor, is valuable information for those engaged in synthetic manipulation of hydroperoxides. cis-Aldehyde 3, the expected product from the fragmentation of β-hydroxy hydroperoxide 2, was synthesized through the oxidative cleavage of diol 4 by lead tetraacetate (Scheme 5).26 trans-Aldehyde 10 was readily obtained by treatment of 3 with pyridine.27 trans-Aldehyde 10 can be selectively oxidized to 4oxo-2-heptenedioic acid 11, a known compound.28 The cisaldehyde 3 reacts with methoxyamine hydrochloride to form an
(Scheme 6). In the presence of pyridine, the β-hydroxy hydroperoxide 2 readily fragmented in CH2Cl2 solution to afford trans-aldehyde 10 (38%) and the reduction product 4 (16%). Treatment of 2 with triethylamine gave only diol 4 (57%) and no fragmentation products. The result supports the involvement of 2 in the mechanism postulated above for the conversion of 1 into 4 upon treatment with triethylamine and further confirms the fact that 2 can be easily reduced. βHydroxy hydroperoxide 2 was partly decomposed when it was incubated in trifluoroacetic acid overnight; however, the yield of aldehyde is very low. Although the β-hydroxy hydroperoxide 2 is stable in CHCl3 or CH2Cl2 solutions, it decomposed in D2O upon incubating at 37 °C for 24 h to form aldehyde 3 (as a hydrate in water) and diol 4 (Table 2). It is tempting to speculate that the effect of a strongly polar protic solvent indicates a polar mechanism for the decomposition in water. However, hydroperoxides are known to undergo transition-metal-ion-mediated decomposi1555
dx.doi.org/10.1021/jo201910g | J. Org. Chem. 2012, 77, 1554−1559
The Journal of Organic Chemistry
Note
Table 2. Metal-Ion-Promoted Decomposition of 2a unreacted
a
catalyst (in D2O)
reaction time
PBS buffer (200 mM) Fe3+ (3.6 mM) Cu2+ (3.6 mM)
24 h 0.5 h 0.5 h 0.5 h
2
Table 3. Vitamin E- and C-Promoted Fragmentation of 2 unreacted (%)
product yields (%) 3b
4
43 15 70 80
11 30 5 9
reagents (slovent)a Vit E (CH3CN) Vit E, Fe2+(CH3CN) Vit E, Cu2+ (CH3CN) Fe2+ (CH3CN) Cu2+ (CH3CN) Vit C (D2O) Vit C, Fe3+ (D2O) Vit C, Cu2+ (D2O)
36 mM at 37 °C. bAs the hydrate 13.
tion through single electron transfer, leading to the formation of an alkoxy radical.31,32 Possibly, there are traces of metal ions in water that are sufficient to promote the fragmentation (vide infra). The formation of diol 4 from the β-hydroxy hydroperoxide 2 may also involve homolytic cleavage of the hydroperoxide, promoted by trace metal ions, that generates an alkoxy radical that abstracts hydrogen or an alkoxide that abstracts a proton. Alternatively, β-scission of the alkoxy radical can result in the formation of cis-aldehyde 3 (Scheme 7). In aqueous solution, water adds to an aldehyde carbonyl in 3 to form a hydrate 13.
reaction time, temperature 4 h, 25 °C 4 h, 25 °C
2
3b
10
96
4 26
14
4 h, 25 °C 4 4 3 5 5
h, 25 °C h, 25 °C h, 37 °C min, 25 °C min, 25 °C
product yields (%) 4
36 99 98
1 2 35 65 66
13 15 13
a The concentration of vitamin E (or C)/2/metal ions = 1.5:1:0.1. bAs the aldehyde hydrate 13.
Cu2+). When reacted at room temperature for 4 h, β-hydroxy hydroperoxide 2 with only vitamin E or catalytic amounts (0.1 equiv) of metal ions (Fe2+, Cu2+) gave very low yields (
