Atropisomer hamatine

Compound 1 was the major alkaloid present and compounds 2 and 3 were previously unknown as natural products. The related naphthylisoquinoline alkaloids ancistrocladine (5) and its atropisomer hamatine (6) were previously known from other Asian Ancistrocladus species [25] while the 7,3 -linked naphthyl-isoquinoline, ancistrotectorine (8), has been previously isolated from Ancistrocladus lectorius from Thailand [26]. The structure of I was deduced from spectral data (UV, MS, NMR) as well as by its ready conversion to the known 2 through successive mesylation and LiAIH4 reduction. Likewise the structure and relative stereochemistry of 4 were established by spectral analysis (HMBC, NOESY) and by conversion to the known (-)-N-formyl-O-methylancistrocladine derivative 7 via successive formylation followed by methylation (Mel, NaH-DMF). 

With the optically active tetrahydroisoquinoline 79 in hand the total synthesis of (-)-ancistrocladine (1), and its naturally occurring atropisomer (-t-)-hamatine (92), was completed as shown in Scheme 11. Esterification of compound 79 with acid chloride 60 gave the ester 87 which smoothly underwent Pd(II) catalysed intramolecular coupling to yield the 5-1 coupled lactones 88 and 89 as a 3 1 mixture respectively. None of the possible 7-1 linked regioisomeric lactone was detected. These lactones are helicene-like atropisomers (not axially prostereogenic) but they... 

Compound 93 can be converted into hamatine (92) by reductive cleavage of the ether bridge with dilithio biphenyl followed by catalytic hydrogenolysis on the Af-benzyl group. Re-epimerisation of 93 in solution at room temperature then gives the same thermodynamic ratio from which 94 is separated and can converted into 1. Thus, a chirally economical synthesis of each atropisomer is achieved. 

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