The Total Synthesis of (±)-Ochrobirine

Abstract

<p>The spirobenzylisoquinoline alkaloids form a group of twelve bases incorporating a ring system which has only recently been recognized. The total synthesis of several of them has been realized. A new route to the spirobenzylisoquinolines is described here and differs from those previously reported. The readily available 2-phenyl-1,3-indandiones were used as starting materials and the synthesis of the spiro system was completed by construction of ring B through a modified Pomeranz-Fritsch reaction. The introduction of the nitrogen and the two carbons required to complete the carbon framework was achieved through bromination followed by displacement of bromine by aminoacetaldehyde diethyl acetal. Acid cyclisation after protection of the nitrogen completed the synthesis of the spiro system. The scheme was tested using 2-(3,4-dimethoxyphenyl)-1,3-indandione to give an analogue of ochrobirine. (±)-Ochrobirine, a member of the spirobenzylisoquinoline alkaloids, was then synthesized according to the scheme outlined.</p> <p>During the course of this work, two rearrangement of the spirobenzylisoquinoline system were observed. The first offers a route to the phthalide isoquinoline alkaloids while the second provides a route to the protoberberine alkaloids. A possible mechanism for the two rearrangements is offered. In the light of the results obtained from this work and of those from the work of others, a model for the biogenesis of the spirobenzylisoquinoline is proposed.</p>