A Simple, Convenient, Highly Regioselective Synthesis of Isobenzofuran- 1(3H)-ones (phthalides) as well as Maculalactone A & B, the Bioactive Butyrolactones

Author(s): Soumen Joardar, Santanu Chakravorty, Sakti P. Das.

Journal Name: Letters in Organic Chemistry

Volume 13 , Issue 2 , 2016

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Abstract:

Bacground: Among the class of oxygen heterocycles, the benzoannulated lactone (3H -isobenzofuran- 1-one or phthalide) moiety is found in many natural products. Phthalides possess a wide range of biological activity e.g. (-)-Hidrastine is active at the human opioid receptor known as CCR5, while fuscinarin interferes with HIV entry into cells. Phthalides also represent an important structural subunit in numerous natural products that exhibit a wide range of biological activities, such as antispasmodic, antifungal, vasodilators, and coronary artery dilators. Except their biological activities, phthalides are also versatile starting material for the synthesis of various important organic compounds, including the key intermediates in the synthesis of functionalized naphthalenes and anthracenes, which in turn are used as synthons for tricyclic and tetra cyclic aromatic natural products. The present communication describes a simple but efficient and expedient one pot strategy for the synthesis of phthalides.

Methods: Diethyl phthalate was considered initially for the cyclization strategy using different metal hydrides at variable temperatures. The reaction was carried out at -30°C with 2.5 equivalent of DIBAL-H, the phthalide was obtained in ~68% yield along with minor amount of alcohol (~10%) and the unreacted starting material (~12%). In the reaction protocol, other solvents such as tetrahydrofuran, diethyl ether, and chlorobenzene were found to be effective in cyclization at -30°C. But yield of the phthalide was observed to be less compare to CH2Cl2. Further decrease of the reaction temperature up to - 78°C showed no effect on the yield of cyclized product. Use of 3 equivalent of DIBAL-H dramatically decreases the yield of the cyclized product (30%) and increased the amount of reduced product (60%).

Results: The promising outcome of the above observations encouraged us to study the general scope and limitations of this protocol for the reduction of different substituted phthalides. It was found that diethyl esters of nitro-, bromo-, 4'- methyl-biphenyl-, 3'-methyl-biphenyl-, 2'-methyl-biphenyl-, biphenyl-, 4-pyrazin-2-yl-, and 4-(4-methyl-thiazol-5-yl)- substituted phthalic acids readily underwent reduction with DIBAL-H to afford the corresponding phthalides in moderate to good yields.

Conclusion: We developed a simple, convenient, one step protocol for the synthesis of isobenzofuran-1(3H)-ones (phthalides) from phthalate esters in moderate to good yields. We have also demonstrated a short and effective route to prepare two bioactive butyrolactones, viz., maculalactone A & B. In our opinion, the present approach is general in nature and could be useful to design diverse butyrolactone skeletons.

Keywords: Bioactive butyrolactones, DIBAL-H, maculalactones, phthalides, regioselective synthesis.

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Article Details

VOLUME: 13
ISSUE: 2
Year: 2016
Page: [127 - 134]
Pages: 8
DOI: 10.2174/1570178613666151124200300
Price: $65

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