HETEROCYCLES

Note | Regular issue | Vol. 81, No. 6, 2010, pp. 1485-1491
Received, 2nd March, 2010, Accepted, 22nd April, 2010, Published online, 23rd April, 2010.
DOI: 10.3987/COM-10-11937

■ A Synthesis of β-Allyl Substituted Isotetronic Acid Derivatives via Thermal Claisen Rearrangement

Xiaping Ma, Zhiming Li, and Quanrui Wang*

Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China

Abstract

Isotetronic acids are of great interest in agricultural and pharmacological research and occur in a number of natural products. This paper describes the first Claisen rearrangement of the O-allyl substituted isotetronic acids 2 under thermal conditions furnishing the β-allyl substituted isotetronic acid derivatives 3 in high yields.

Isotetronic acid derivatives posses as a common feature the central 2-(5H)-furanone unit I substituted with hydroxy or alkoxy groups at position 3 (Figure 1). They have frequently been isolated from a variety of natural sources and recognized as a kind of important butenolides.1,2 A wide spectrum of biological activities has been reported. For example, WF-3681 produced by Chaetomella raphigera has been reported to be an effective aldose reductase inhibitor.3 Many other isotetronic acids are found to be useful as anti-oxidants and anti-inflammatory agents,4 inhibitors of CDKs,5 anti-depressants and perfumes.1 Isotetronic acid derivatives have also been used as synthetic building blocks during the synthesis of tetrodotoxin, 6 6-thiosialic and neuraminic acid.7 Although a number of synthetic approaches to this class of compounds have been reported,1,5,8 the development of new and practical methods that can create structural diversity is of considerable interests. During the course of our study, we recently have shown that O-protected isotetronic acid derivatives can be achieved via an expedient DBU/Et3N-mediated sequential homoaldol-lactonization-alkylation reactions of ethyl pyruvate with various electrophiles.9 The protocol carries several notable advantages such as the wide substrates, simple operation, exceedingly mild condition and no use of any expensive reagents.
The aliphatic Claisen rearrangement is a [3,3]-sigmatropic rearrangement in which an allyl vinyl ether is converted thermally to an γ,δ-unsaturated carbonyl compound.10 Depending on the type of allyl vinyl ethers, a great number of carbonyl compounds can be produced. Consequently, many chemists aspired to employ a Claisen rearrangenment in a key carbon-carbon bond-forming step, attesting to the synthetic power of this kind of reaction.11 In continuation of our work in the synthesis of novel isotetronic acid compounds, we wish to report herein that the 3-OH allyl-protected isotetronic acids 2 can readily be elaborated to β-allyl substituted isotetronic acids via the thermal aliphatic Claisen rearrangement.

The synthetic strategy is outlined in Scheme 1. First, the 3-O-protected isotetronic acids 2 required as our key starting material were synthesized using our recently established method.9 Thus, ethyl pyruvate 1 was allowed to react with different allyl halides by employment DBU along with Et3N as the base (equivalent ratio 0.20:0.85). The base-couple-mediated sequential homoaldol-lactonization-allylation reactions provided the O-protected isotetronic acid derivatives 2 in 80-85% yield.
With the 3-O-protected isotetronic acids 2 on hand, the Claisen rearrangement reactions were attempted. We chose 4-allyloxy-2,5-dihydro-2-methyl-5-oxo-2-furancarboxylic acid ethyl ester 2a as a model substrate to test the reactivity. After careful optimization of the reaction conditions, 2a was successfully rearranged to the β-allyl substituted isoletronic acid 3a. In a typical protocol, 0.5 mmol 2a in toluene was heated in a sealed tube at 170 °C for 22 h. Usual work-up on the resultant mixture afforded 3a in 86% yield. The effect of solvent on the reaction was also briefly examined. We found that toluene is the best choice for the reaction whereas other solvents such as benzene xylene, and N,N-dimethylaniline were inappropriate for the reaction or caused a severe deterioration in yield.

It has been reported that the Claisen rearrangement can be performed under milder conditions with aid of the use of a transition metal salt like Pd(OAc)2.12 Based on this view, we also investigated the reaction of 2a under the catalysis of Pd(OAc)2. A set of different condition combinations were attempted, but all failed to facilitate the reaction. Thus, for example, treatment of 1a in CH2Cl2 at room temperature for overnight, no reaction occurred in the presence of 2% or 5% mmol Pd(OAc)2. Increasing the dosage of Pd(OAc)2 to 10% mmol didn’t show any beneficial effect on promoting the rearrangement. Switching the solvent to CH3CN, toluene, xylene and THF the reaction were still unsuccessful at ambient conditions. Thus, the thermal condition was determined to be our choice.
The preparative scope of our methodology was investigated under the above optimal thermal conditions: heating 0.5 mmol 2 in toluene as solvent in a sealed tube for a specific time. As exhibited in Table 1, the reaction proceeded smoothly under comparable conditions and seems to tolerate a wide range of substrates with different substitution pattern on the allyl moiety. The pure products 3a-e could be obtained by column chromatography (eluent: EtOAc/PE) in 70–86% yields (Table 1, entries 1-5). It is worthy to note that the protocol is equally applicable to the cyclohex-2-enyloxy substituted isotetronic acid 2e, which delivered the corresponding rearranged product 3e in a moderate yield (Table 1, entry 5).

Interestingly, the 3,3-dimethyl substituted allylic counterpart 2f took a more complicated course, leading to the abnormal formation of the 3-methylbut-3-en-2-yl substituted analogue 3f' and unassigned amount of the 3-methylbut-2-en-2-yl isomer 3f'' as evidenced by GC and NMR. Although the mechanistic detail is a blur at present stage, a plausible rationale accounting for the formation of 3f' and 3f'' is depicted in Scheme 2.13 Under the standard condition, 2f underwent the normal Claisen rearrangement leading to product 3f, which may be instable and cannot survive the condition. Instead, 3f would undergo a consecutive intramolecular Conia-type oxa-ene reaction leading to the formation of the spiro intermediate 4. Compound 4 experienced a further retro-Conia-ene type reaction to afford the isolated isotetronic acid 3f' with concurrent cyclopropane ring opening and regeneration of an olefinic double bond. Formation of 3f'' is tentatively accounted for by a consecutive [1.3]-H shift followed by a keto-enol tautomerisation.13

A limitation was observed when we try to extend the reaction to the propargylic vinylic compound 2g. Under our conditions, formation of the expected allenic product 3g couldn't be detected (Table 1, entry 7).
In summary, the Claisen rearrangement reaction of a series of the 3-OH allyl-protected isotetronic acids 2 was successfully performed under heating conditions. We believe that this protocol provide a reliable synthetic way to β-substituted isotetronic acid derivatives with high yields.

EXPERIMENTAL
NMR spectra were recorded on a JEOL ECA-400 spectrometer operating at 400 MHz for proton, and 100 MHz for carbon. 1H chemical shifts (δ) are reported in ppm relative to TMS as internal standard. 13C chemical shifts were internally referenced to the deuterated solvent signals in CDCl3 (δ 77.00 ppm). Mass spectra were recorded on a HP 5989A mass spectrometer. High-resolution mass spectra data were measured with a Bruker micrOTOF II instrument.
General Procedure:
In a sealed tube was placed a solution of 2 (0.5 mmol) in dry toluene (8 mL), and the mixture was stirred under heating at 170 °C for 22 h. The resultant mixture was cooled to rt, and the solvent was removed at reduced pressure. The residue was dissolved in CH2Cl2 (5 mL), washed twice with water, dried over MgSO4, filtered, and concentrated under high vacuum. The crude product was subjected to flash column chromatography on silica gel with a 1:3 mixture of EtOAc-PE, affording pure 3 as highly viscous yellow oil.
3-Allyl-4-hydroxy-2-methyl-5-oxo-2,5-dihydrofuran-2-carboxylic acid ethyl ester (3a): Pale yellow oil. IR (CH2Cl2): 3323, 1786, 1743, 1650 cm-1; 1H NMR (400 MHz, CDCl3): δ 5.83-5.79 (1 H, m, C=CH-), 5.16-5.12 (2 H, m, CH2=C), 4.17 (2 H, q, 3J = 7.32 Hz, OCH2), 3.09 (2 H, d, 3J = 6.88 Hz, C=C-CH2), 1.69 (3 H, s, CH3), 1.27 (3 H, t, 3J = 7.32 Hz, CH2CH3); 13C NMR (100 MHz, CDCl3): δ 169.1, 168.5, 139.1, 134.6, 131.1, 118.2, 84.9, 62.6, 29.2, 21.2, 14.1; MS (EI): m/z 226 [M+, 100%]. HRMS (ESI): calcd for C11H14O5+Na 249.0739, found 249.0731.
4-Hydroxy-2-methyl-3-(2-methylallyl)-5-oxo-2,5-dihydrofuran-2-carboxylic acid ethyl ester (3b): Pale yellow oil. IR (CH2Cl2): 3321, 1786, 1745, 1655, 1379 cm-1; 1H NMR (400 MHz, CDCl3): δ 4.85 (1 H, s, HCH=C), 4.77 (1 H, s, HCH=C), 4.15 (2 H, q, 3J = 7.32 Hz, OCH2), 3.06-3.01 (2 H, m, C=C-CH2), 1.75 (3 H, s, CH3), 1.70 (3 H, s, CH3), 1.26 (3 H, t, 3J = 7.32 Hz, CH2CH3); 13C NMR (100 Hz, CDCl3): δ 169.1, 168.5, 140.2, 139.1, 131.1, 113.4, 84.9, 62.6, 32.3, 29.7, 21.2, 14.0; MS (EI): m/z 240 [M+, 100%]. HRMS (ESI): calcd for C12H16O5+Na 263.0895, found 263.0896.
3-(But-3-en-2-yl)-4-hydroxy-2-methyl-5-oxo-2,5-dihydrofuran-2-carboxylic acid ethyl ester (3c): Pale yellow oil. IR (CH2Cl2): 3323, 1786, 1742, 1655, 1380 cm-1; 1H NMR (400 MHz, CDCl3): δ 5.78-5.74 (1 H, m, C=CH), 5.06-5.01 (2 H, m, C=CH2), 4.22 (2 H, q, 3J = 7.32 Hz, OCH2), 3.20 (1 H, m, -CH), 1.75 (3 H, s, CH3), 1.28-1.25 (6 H, m, 2 CH3); 13C NMR(100 Hz, CDCl3): δ 170.2, 168.5, 139.1, 137.5, 131.1, 114.1, 84.9, 62.6, 18.1, 22.1, 21.2, 14.0; MS (EI): m/z 240 [M+, 95%]. HRMS (ESI): calcd for C12H16O5+Na 263.0895, found 263.0893.
4-Hydroxy-2-methyl-5-oxo-3-(1-phenylallyl)-2,5-dihydrofuran-2-carboxylic acdi ethyl ester (3d): Yellow oil. IR (CH2Cl2): 3323, 1786, 1743, 1655, 1600, 1380 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.31-7.24 (5 H, m, Ph), 6.31-6.27 (1 H, m, C=CH), 5.21-5.11 (2 H, m, C=CH2), 4.20 (2 H, q, 3J = 7.32 Hz, OCH2), 3.77-3.73 (1 H, m, CHPh), 1.76 (3 H, s, CH3), 1.28 (3 H, t, 3J = 7.32 Hz, CH3); 13C NMR (100 Hz, CDCl3): δ 169.1, 168.5, 143.2, 139.1, 140.6, 131.4, 130.6, 128.7, 123.2, 117.1, 84.9, 62.6, 43.1, 21.4, 14.0; MS (EI): m/z 302 [M+, 90%]. HRMS (ESI): calcd for C17H18O5+Na 325.1052, found 325.1048.
3-(Cyclohex-2-enyl)-4-hydroxy-2-methyl-5-oxo-2,5-dihydrofuran-2-carboxylic acid ethyl ester (3e): Yellow oil. IR (CH2Cl2): 3320, 2875, 1786, 1745, 1655 cm-1; 1H NMR (400 MHz, CDCl3): δ 5.91 (1 H, t, 3J = 6.88 Hz, CH2CH=), 5.54 (1 H, dd, 3J1 = 6.8 Hz, 3J2 = 6.9 Hz, CH=C), 4.21 (2 H, q, 3J = 7.32 Hz, OCH2), 3.12-3.10 (1 H, m, C=C-CH), 1.78-1.70 (9 H, m, 3 CH2 & CH3), 1.27 (3 H, t, 3J = 7.32 Hz, CH3); 13C NMR (100 Hz, CDCl3): δ 174.2, 169.1, 138.2, 136.6, 130.1, 129.8, 126.2, 84.6, 62.6, 32.9, 26.9, 24.5, 21.5, 14.1; MS (EI): m/z 266 [M+, 93.8%]. HRMS (ESI): calcd for C14H18O5+Na 289.1052, found 289.1054.
4-Hydroxy-2-methyl-3-(3-methylbut-3-en-2-yl)-5-oxo-2,5-dihydrofuran-2-carboxylic acid ethyl ester (3f'): This compound was only obtained as yellow oil in unpurified form that contains unassigned amount of the isomer 3f''. IR (CH2Cl2): 3320, 1786, 1742, 1655, 1379 cm-1; 1H NMR (400 MHz, CDCl3): δ 5.97 (1 H, OH), 4.89 (1 H, s, HCH=C), 4.79 (1 H, s, HCH=C), 4.21 (2 H, q, 3J = 7.32 Hz, OCH2), 3.07-3.03 (1 H, m, -CH), 1.78 (3 H, s, CH3), 1.70 (3 H, s, CH3), 1.28-1.24 (6 H, m, 2 CH3); 13C NMR (100 Hz, CDCl3): δ 169.1, 168.5, 141.1, 139.1, 131.2, 112.2, 84.9, 62.6, 32.3, 21.5, 21.2, 18.6, 14.1; MS (EI): m/z 254 [M+, 70%]. HRMS (ESI): calcd for C13H18O5+Na 277.1052, found 277.1046.

ACKNOWLEDGEMENTS
The authors thank Prof. G. Fráter and Dr. A. Goeke from Givaudan Schweiz AG for their valuable suggestions.

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