강력한 항암 활성 Isocarbostyril 알칼로이드인 (+)-trans-Dihydronarciclasine의 입체선택적 전합성

Abstract

We have achieved a highly stereoselective and efficient total synthesis of trans-dihydronarciclasine from a readily available chiral starting material. Our scheme defines two of the five stereogenic centers of the natural product by an amino acid ester-enolate Claisen rearrangement. The other three stereogenic centers are created in a highly stereocontrolled fashion via a six-membered-ring vinylogous ester intermediate, which is generated from the γ,δ-unsaturated ester functional group of Claisen rearrangement product in an efficient three-step sequence. This concise total synthesis exemplifies the use of a highly regioselective Friedel-Crafts-type cyclization to form the B-ring via an isocyanate intermediate derived from an N-Boc group, which is superior to the conventional method using an imino triflate intermediate. This mild and regioselective reaction conditions are also applicable for synthesis of various substituted isoquinolin-1-ones, β-carbolines, thiophen fused ring systems and tetrahydrobenzoazepin-1-ones. Acid additives, such as BF3•Et2O, extend the application of the method to substrates bearing less nucleophilic aryl moieties by enhancing the Friedel-Crafts-type cyclization of isocyanate intermediates.