A study of Heck cyclization reactions to form phenanthridine ring systems

Abstract

We thank the EPSRC (DTA award to LRD), GlaxoSmithKline, and the SCI (Messel Scholarship to LRD) for financial support of this work. Supporting information: Experimental for cyclizations in Table 2, 3 and 4. Confirmations of double bond isomers and ring junction stereochemistry. 1H and 13C Spectra for all compounds. 1H NMR integrals supporting ratios in Tables 2, 3 and 4.

A Ring Rearrangement Approach to the Synthesis of Benzo[b]quinolizine and Benzoindolizine Architectures

“…3 The reactions are conducted using a Grubbs metathesis catalyst under an ethylene atmosphere. We recently disclosed novel methodology for the rapid and efficient synthesis of cis-ring fused phenanthridine double bond isomers 4a ( 1,2 alkene), 4b ( 2,3 ) and 4c ( 3,4 ) in excellent yield using the Heck reaction (Scheme 2). 4 The phenanthridine core lies at the heart of many bioactive natural products including the antitumour antibiotic pancratistatin, 5 antiviral lycorine, 6 and the tubulin polymerisation inhibitor chelidonine.…”

“…We recently disclosed novel methodology for the rapid and efficient synthesis of cis-ring fused phenanthridine double bond isomers 4a ( 1,2 alkene), 4b ( 2,3 ) and 4c ( 3,4 ) in excellent yield using the Heck reaction (Scheme 2). 4 The phenanthridine core lies at the heart of many bioactive natural products including the antitumour antibiotic pancratistatin, 5 antiviral lycorine, 6 and the tubulin polymerisation inhibitor chelidonine. 7 As part of our ongoing efforts towards the synthesis of a small library of naturalproduct-like analogues derived from this interesting core structure, 8 we have investigated the application of an cycloalkene-yne RRM protocol to N-propargyl derivatives (5a-c) of these alkene isomers.…”

“…Heck cyclisation approach to the phenanthridine core. 4 P = Boc, Cbz, SO 2 Me. 4a= 1,2 ; 4b= 2,3 ; 4c= 3,4…”

“…However, we found that the substrate was not compatible with either of the Heck cyclisation protocols we had developed in our previous work. 4 As a result we examined direct deprotection of the isolated Boc-phenanthridine double bond isomers 4a-c, followed by N-propargylation (Table 1).…”

“…Scheme 3 Proposed RRM of the phenanthridine double-bond isomers. 5a = D 1,2 ; 5b = D 2,3 ; 5c = D 3,4 .…”