Opium alkaloids. Part XVI. The biosynthesis of 1-benzylisoquinolines in Papaver somniferum. Preferred and secondary pathways; stereochemical aspects

Abstract

Tetrahydropapaverhe (VI), derived from (-)-nor-reticuline ( 11) and (-)-nororientaline (111), is the principal immediate precursor of papaverine ( V I I I ) in Papaver somniferum. The trimethyl ethers of papaveroline ( X I a ) and b) are incorporated less effectively into papaverine, the dimethyl ether ( X I c ) not a t all. Norprotosinomenine ( I V ) and noriso-orientaline(V) can also be biotransformed into papaverine in the plant, but this occurs by an aberrant route which does not involve tetrahydropapaverine as an intermediate.The stereoselectivity of various 0-and N-methylations and of dehydrogenation of tetrahydropapaverine is discussed. ' Unnatural ' (-) -1audanosine w a s biosynthesized from ' unnatural ' (+)-tetrahydropapaverine, but could not be obtained from ' unnatural ' (+)-nor-reticuline. Enzymic racemization of benzyltetrahydroisoquinolines, which is a prerequisite for thelbiosynthesis of morphine alkaloids. appears to be limited to reticuline (Xa). N-Methylations may occur at several stages along the biosynthetic routes, and there is evidence that enzymatic N-demethylations may take place to an appreciable extent. PAPAVERINE (VIII) had been shown to be biosynthesized in the opium poppy from tyrosine 1$ via 3,4-dihydroxyphenylalanine (DOPA) and norlaudanosoline (I) as proposed originally by Winterstein and Trier * in 1910.In an earlier paper we reported that nor-reticuline (11) was an efficient precursor of papaverine, and the question arose as to the sequence of O-methylation and the stage at which aromatization of ring B takes place.

The biosynthesis of papaverine proceeds via (S)-reticuline

“…The intermediate is ( S )-tetrahydropapaverine, a compound first postulated in papaverine biosynthesis (Brochmann-Hanssen et al, 1971) after it had been found as a natural product isolated from P. somniferum . This postulate was verified by Brochmann-Hanssen et al (1975) who synthesized (−)-tetrahydropapaverine that was found to be incorporated into papaverine with an, at that time, extremely high incorporation rate in the poppy plant. However, the opinion was that ( S )-norreticuline and norlaudanosoline are the precursors of norlaudanine, norlaudanosine, with the biosynthetic grid ending with tetrahydropapaverine and papaverine (Battersby, 1963; Brochmann-Hanssen et al, 1971; Uprety et al, 1975) but, as mentioned before, Brochmann-Hanssen and associates never found norreticuline, norlaudanine or norlaudanosine.…”

“…This hypothetical intermediate was seemingly verified when it was shown that the expected labeled precursors were incorporated into papaverine, the target compound (Battersby and Harper, 1959,1962; Battersby et al, 1964), despite some discrepancies in the labeling patterns (for review see Spenser, 1969) produced in poppy and other isoquinoline alkaloid accumulating plants. Extensive phytochemistry, precursor synthesis and experimentation by Brochmann-Hanssen and associates (Brochmann-Hanssen and Furuya, 1964; Brochmann-Hanssen et al, 1965; Brochmann-Hanssen et al, 1971; Brochmann-Hanssen et al, 1975) not only discovered the now recognized true precursors of papaverine, the opium poppy-derived laudanine (laudanidine) and laudanosine alkaloids, but found in labeled ( S )-tetrahydropapaverine an excellent precursor for papaverine while ( R )-tetrahydropapaverine is largely inactive. However, ( R,S )-reticuline was very poorly incorporated into papaverine, but most importantly the highest incorporation rates into papaverine were achieved with norreticuline, which is missing the N -methyl group.…”

“…This promiscuity was demonstrated by us when poppy seedlings were fed with [1- 13 C]-( S )-norreticuline, which resulted in the formation of singly labeled ( S )-reticuline and singly labeled thebaine, from which we found a ratio of 0.01 for the quotient of labeled to unlabeled compound. Supporting this is the fact that the unnatural alkaloid nororientaline is an excellent precursor to papaverine since presence of the 7- O -methyl group prevents funneling into the thebaine pathway (Brochmann-Hanssen et al, 1975). …”

“…The latter, however, was claimed to be not significantly incorporated into papaverine due to the lack of an unmethylated phenolic hydroxyl group (Battersby et al, 1964). Independently, the group of Brochmann-Hanssen (Brochmann-Hanssen et al, 1971; Brochmann-Hanssen et al, 1975; Brochmann-Hanssen et al, 1980) extended these suggestions and claimed that norreticuline, norlaudanine and norlaudanosine are well incorporated into papaverine while reticuline is not (Uprety et al, 1975). This proposal receives support by the recent claim that a SAM-dependent O -methyltransferase exists that accepts norreticuline as the sole substrate (Pienkny et al, 2009).…”

Benzylisoquinoline alkaloid biosynthesis in opium poppy

“…1). The efficient incorporation of radiolabeled N-desmethyl compounds (Brochmann-Hanssen et al 1975;Uprety et al 1975) and the identification of a norreticuline 7-O-methyltransferase (N7OMT), which accepts only norreticuline yielding norlaudanine (Pienkny et al 2009), provides biochemical support for the N-desmethyl pathway. A recent study using mass spectrometry and heavy stable-isotope labeling of (S)-reticuline, (S)-laudanine and (S)-laudanosine suggested that N-methylated 1-benzylisoquinolines are incorporated into papaverine at low levels (Han et al 2010), providing some support for the N-methyl pathway.…”