Studies towards the synthesis of the clavepictines

• Main Author: Hancox, T. C.
• Published: University of Cambridge 1997
• Subjects: 547.7
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.603647

Quinolizidine alkaloids, exemplified by lupinine 3, abound in nature and have attracted a good deal of synthetic interest due to the biological activity associated with this generic class of compound. Chapter 1 reviews methods for the construction of quinolizidine alkaloids. Emphasis is placed on the key quinolizidine forming reaction and the methods are grouped according to this criterion. Chapter 2 includes a brief review of the asymmetric imine Diels-Alder reaction. The utility of this reaction is then demonstrated by the preparation of azabicyclo[2.2.2]octenes in racemic and homochiral forms and their elaboration to 3,6-<I>cis</I> disubstituted piperidines. The bicyclic alkene 385 was prepared by an efficient imine Diels-Alder reaction between the imino acetate 336 and the diene 384. The cycloadduct 385 was obtained as a single enantiomer by resolution <I>via </I>formation of the pantolactone ester 399. (Fig. 10279A). Chapter 3 describes efforts directed towards the total synthesis of the anti-tumour alkaloids clavepictine A 171 and clavepictine B 170. The route exploits the imine Diels-Alder reaction described above to create three of the chiral centres. The final chiral centre is derived from a coupling of the aldehyde 466 and the ylide of the phosphonium salt 478, available in 4 steps from (<I>S</I>)-butane-1,2,4-triol. A synthesis of the quinolizidine 491 is outlined. Chapter 4 describes methodology developed with the specific aim of forming a carbon-carbon bond in 2-piperidinemethanol derivatives of the general structure 500. The incentive was provided by a problem encountered in studies towards the synthesis of clavepictine. The sulphamidate 516 was prepared in 2 steps from 2-piperidinemethanol and was found to react with dialkyl cuprates to afford piperidines such as 515. Efforts directed towards the extension of this methodology to those cuprates derived from the functionalised iodides 526, 527 and 573 is discussed. (Fig. 10279B).