Abstract
This study describes the stereoselective synthesis of two new γ-lactones in 6 and 3 steps and 19 and 32% yield, respectively, directed toward the total synthesis of the natural product (−)-cleistenolide. The starting material was an enantiomerically pure diacetonide diol, derived from d-mannitol with the required stereocenters for (−)-cleistenolide synthesis. γ-Lactone syntheses were based on highly selective protection and deprotection of hydroxyls from d-mannitol. The formation of γ-lactone rings was the culmination of this approach, made possible by a Horner-Wadsworth-Emmons Z-olefination between diacetal aldehyde and ethyl 2-(bis(o-tolyloxy)phosphoryl)acetate to produce an unsaturated ester. The Z-isomer ester was highly favored in relation to the E-isomer (Z/E ratio of 94:6), allowing the formation of the γ-lactone ring under acid catalysis. This strategy precluded the use of chiral auxiliaries or catalysts for the control of stereocenters in the novel γ-lactones.
Highlights
The current study reports an unprecedented approach for the stereoselective synthesis of two γ-lactones whose stereocenters originated from d-mannitol
Retrosynthetic analysis[29] revealed that (−)-1 is derived from γ-lactone 4 or, alternatively, γ-lactone 5 (Scheme 1)
Rearrangement of γ-lactone 4 to d-lactone (−)-1 should be achieved by a three-step, one-pot sequence: reduction of the carbonyl with diisobutylaluminium hydride (DIBAL-H), treatment of the respective lactol with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and concomitant [1,4]-silyl transfer, and oxidation of the lactol, followed by disilylation and the respective esterifications. γ-Lactone 4 can be prepared from Z-olefin 6 by a five-step sequence
Summary
(−)-Cleistenolide (1) is an exponent of the class of 5,6-dihydro-2H-pyran-2-ones.[1,2,3] It contains a d-lactone ring, a moiety found in the structure of several natural products with expressive antibiotic properties and anticancer activity against a broad spectrum of tumor cells.[4,5,6,7,8,9,10,11,12,13,14] (−)-1 and the polyoxygenated compound cleistodienol (Figure 1) were isolated by Samwel et al.[15] in 2007 from Cleistochlamys kirkii (Benth.) Oliv. The yellowish residue was purified by column chromatography (SiO2, hexane/EtOAc 90:10 → 60:40) to give 9 in 23% yield and recover 4% of the starting material 10.
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