A Simple Synthesis of Amphimedine

Amphimedine may be synthesised in sin simple steps from the readily amilable arafluorenone (2).Amphimedine ( 1) is one of a number of pentacyclic alkaloids ~ecently isolated from marine 1-3 1 sources .Because of its general cytotoxicity , we were interested in devising a synthesis that would generate intermediates that might possess more specific anti-tumor praperties.We have communicated our synthesis at a conference4, and recently reported syntheses of amphimedine by 5 Echavarren and stille5 and Kubo and Nakahara prompt u .ta report our quite diffe~ent approach.The fluorenone (2)6-7 was silylated and treated with 4-pyridylllthium at -20.C to give the fluorenol ( 3 ) ' in 87% yield.By analogy with our previous work7, we were confident that reaction of (3) with hydrazaic acid would result in migration only of the most electron-rich benzene ring (cf 4), to give the desired diaraphenanthrene (5), mp 327-32aPC, which was isolated in 69% yield.Conversion of (5) to the chlorapyridine (61, mp 227-22BsC was achieved (90%) with phospholvs oxychloride and dimethylfomamide in phosphorus trichloride.Of Che three nitrogen atoms in (61 that on the pyridine ring w s methylated exclusively with one equivalent of methyl fluorosulfonate, and alkaline ferricyanide oxidation then led cleanly to ( 7 ) , mp 280-28Z°C (deconp), which was converted to the nitrile (8) by reaction with cuprous cyanide in hot dimethyl sulforide.Finally, reaction of (8) with hot PPA gave amphimedine (1).mp 3. 3409C, with identical spectroscopic properties (ir, uv, nmr) as chose kindly provided by Pzl~fesgor F.J. Schmitz.Prior hydrolysis of the nitrile to the acid, followed by cyclisation proved tc be nore eff~cient.~The route described herein is short and efficient, using readily available reagents.A nunrbezl of analogues of [2) and 9(5) have been subjected to cytotoricity and mutagenic activiay studkeg .The compounds showed little mutagenicity activity using the hypoxanthine-guanine phosphortbosyl t~ansferase or cytokinesisblock micronucleus assays.Analogues of (2) showed cytotoxicity, as measured by the frequency of 3 clone-forming cells or blocking of H-thymidine uptake.(a) (i) Me3SiC1, Et3N, THF 60°C, 60 rnin (ii) 4-bromopyridine, BuLi, -40'~-20°c, 2 h , 87% (b) NaN3, PPA, 45'~.20 h, 69%.(c) PC15, M"F (cat.) in POC13, 180'C, 20 h, 90%(dl (i) MeOS02F, 1.3 equiv., ZO'C, 40 min (ii) KOH, K3Fe(CNI6, 2 equiv., 20°C, 10 h, 61%( e ) CuCN, DMSO, 150°C, 4 h, 70%.if) PPA, 9OoC, 5 h, 35%.