Synthesis of (Z)-2-acyl-2-enals via retrocycloadditions of 5-acyl-4-alkyl-4H-1,3-dioxins:: Application in the total synthesis of the cytotoxin (±)-euplotin A
Synthesis of (Z)-2-acyl-2-enals via retrocycloadditions of 5-acyl-4-alkyl-4H-1,3-dioxins:: Application in the total synthesis of the cytotoxin (±)-euplotin A
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DOI：
10.1021/ja011470b
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发表时间：
2001-09-26
影响因子：
15
通讯作者：
Funk, RL
中科院分区：
文献类型：
--
作者：
Aungst, RA;Funk, RL
The 5-acyl-3, 4-dihydro-2H-pyran substructure and its reduced analogue are common to a variety of natural products which possess a diverse array of biological properties (Scheme 1). A well-established strategy for the construction of this key structural unit is via the heterocycloaddition reaction of an unsaturated carbonyl compound, 1 preferably as an activated 3-acyl-1-oxadiene, with an alkene. Many conceivable implementations of this viable approach require the stereocontrolled syntheses of (Z)-2-acyl-2-enals. For example, a projected synthesis of the cytotoxin euplotin A (1) 2 might proceed through an exo cycloaddition (vide infra) of the dihydrofuran moiety with the (Z)-2-acyl-2-enal 2. Unfortunately, methodology for the stereoselective generation of 2-acylenals under the requisite mild conditions is unavailable. 3 We have recently demonstrated that 5-acyl-4H-1, 3-dioxins are viable precursors to 2-acylpropenals via facile retrocycloaddition reactions. 4a The extension of this protocol to the stereoselective preparation of the more highly functionalized (Z)-2-acylenals and its application in the first total synthesis of (()-euplotin A are reported herein.Our initial objective was to examine the stereoselectivity of the retrocycloaddition as a function of the acyl substituent of the 1, 3-dioxin 6 (Scheme 2). To that end, the cyclohexyl imine derivative of commercially available 4H-1, 3-dioxin-5-one was metalated and alkylated to provide the 6-alkyldioxinone 5. Regioselective conversion of ketone 5 to the corresponding lesssubstituted enol triflate was accomplished by kinetic deprotonation with NaHMDS in the presence of N-phenyltrifluoromethanesulfonimide. This enol triflate was then subjected to a variety of palladium-catalyzed carbon monoxide insertion reactions (6a, b, c) as well as a Heck reaction with ethyl vinyl ether (6d) to deliver the desired 5-acyl-4-alkyl-4H-1, 3-dioxins.
