Chirality transfer in an Ireland–Claisen rearrangement: a new approach toward the Iboga alkaloids

Abstract

The synthesis of the isoquinuclidine core of the Iboga alkaloid family is described. This building block contains the entire stereochemical information of the targeted natural products. Starting with ( S)-4-(hydroxymethyl)-4-butanolide, a derivative available in two steps from l-glutamate, ( S)-4-benzyloxy-5,5-dimethoxypentanoic acid was obtained in four steps. Mitsunobu esterification with ( S)-but-3-en-2-ol furnished the inverted ester, which was then subjected to an Ireland–Claisen rearrangement. This crucial step took place with a very satisfactory chirality transfer from the alcohol component to the new carbon backbone of the product. After transformation of the resulting silyl ester function into a hydroxylamino group, the dimethyl acetal moiety was hydrolyzed with 3 M sulfuric acid at 47 °C. Under these conditions, the resulting cyclic nitrone could not be isolated, because it underwent a rapid intramolecular nitrone–olefin [3+2]-cycloaddition reaction to furnish the expected tricyclic isoxazolidine derivative in 67% yield. After chromatographic purification, this product was obtained enantiomerically pure and with a chemical purity of 96%. The targeted isoquinuclidine building block was thus obtained from ( S)-4-(hydroxymethyl)-4-butanolide in 13 steps with an overall yield of 9.2%, which amounts to an average yield of 83.3% per step.