Biosynthesis of boldine (1,10-dimethoxy-6aα-aporphine-2,9-diol)

Abstract

The incorporation of (k) -norprotosinomenine, (*) -nororientalhe, (i) -nor-reticuline, and (i) -reticuline into boldine in Litsea glutinosa has been studied, and the specific utilization of the (*) -reticuline demonstrated. The evidence supports the direct oxidative coupling of (+)-reticdine to give isoboldine, which in turn is shown to be a specific precursor of boldine. The plants also converted norboldine into boldine. Double labelling experiments involving the methoxy-groupof (f) -reticuline showed that most, but not all, of the methoxy-activity was lost in conversion into boldine. BOLDINE (l), the choleretic principle of Peumzls boldzlsMolina, could be formed in nature from suitable l-benzyltetrahydroisoquinoline precursors through various biosynthetic routes. Direct oxidative coupling of reticu-line2 (8) could give rise to the boldine; alternatively oxidative coupling of orientaline (10) and protosinomenine * (12) involving the dienones (15) and ( 16) , respectively, as intermediates, would furnish the required aporphine system by dienone-phenol rearrangement. We now report the details of studies on these and some other aspects of boldine biosynthesis.(&)-Tyrosine was initially fed to young shoots of Litsea glutimsa (Lauraceae), and it was found that the plants were actively biosynthesizing boldine. In subsequent experiments, labelled hypothetical precursors were fed to young L. glutinosa plants. The results of several feedings are recorded in the Table . Feeding (&) -tyrosine Expt.

Halogenated Boldine Derivatives with Enhanced Monoamine Receptor Selectivity

“…We first reexamined the reaction of boldine with Br 2 in acetic acid instead of CCl 4 , assuming that protonation of the nitrogen might hinder the dehydrogenation side reaction, and found that a considerable excess of the halogen was required to achieve high conversions of the alkaloid. Under these conditions, 3,8-dibromoboldine ( 3 ) was obtained in 64% isolated yield, and 3-bromoboldine ( 2 ) in only 9% yield, with chromatographic evidence of the formation of several other products .…”

“…3-Bromoboldine (2): light tan needles from C 6 H 6 ; mp 192−194 °C (lit. 208−209 °C); [α] 18 D +88° ( c 0.11, MeOH); 1 H NMR (DMSO- d 6 ) δ 7.81 (1H, s, H-11), 6.75 (1H, s, H-8), 3.78 (3H, s, O- 10-CH 3 ), 3.50 (3H, s, O- 1-CH 3 ), 3.03 (1H, dd, J = 11.5 Hz, J ‘ = 4.3 Hz, H-5α), 2.97 (1H, dd, J = 13.4 Hz, J ‘ = 3.9 Hz, H-7α), 2.83 (1H, dd, J = 13.4 Hz, J ‘ ≈ 3 Hz, H-6a), 2.69 (2H, m, H-4α and H-4β), 2.39 (3H, s, N- CH 3 ), 2.30 (1H, m, H-5β), 2.26 (1H, dd, J = J ‘ = 13.4 Hz, H-7β); 13 C NMR (DMSO- d 6 ) δ 146.7 (C-2), 146.4 (C-10), 146.3 (C-9), 143.2 (C-1), 129.6 (C-7a), 129.0 (C-3a), 127.3 (C-1a), 125.5 (C-1b), 121.9 (C-11a), 115.3 (C-8), 111.6 (C-11), 110.3 (C-3), 62.4 (C-6a), 60.0 ( O- 1-CH 3 ), 55.8 ( O- 10-CH 3 ), 52.7 (C-5), 43.6 ( N- CH 3 ), 33.4 (C-7), 30.5 (C-4); anal. C 56.34%, H 4.98%, N 3.46%, calcd for C 19 H 20 BrNO 4 , C 56.17%, H 4.96%, N 3.46%.…”

“…These atoms may be expected to contribute to the lipophilicity of the corresponding haloboldines, in terms of log P (where P = the octanol/aqueous buffer partition constant), by values of about 0.62, 0.75, and 1.12, respectively, to be added to the lipophilicity of boldine itself, which we estimate to be considerably less than unity (glaucine, the O,O- dimethyl ether of boldine, is reported to have log P = 1.22) . The bromination of boldine with Br 2 in CCl 4 to afford a mixture of 3-bromoboldine ( 2 ) and 3,8-dibromoboldine ( 3 ) was reported more than 20 years ago . Nevertheless, aporphines are readily dehydrogenated with I 2 to the corresponding 6a,7-didehydro derivatives, presumably via hydrogen abstraction from the benzylic 6a position, to afford a relatively stable free radical 8 and aromatization of ring C.…”

Plants of New Caledonia Part 103.1Alkaloids ofLitsea lecardii

“…The lack of any type of proaporphine leads to consider reticuline as their sole precusor which undergoes an intramolecular ortho-para oxidative coupling according to a well known biogenetic pathway (11). This is supported by feeding experiments on L. glutinosa where such a biosynthesis has been enlighted (12). Here two minor alkaloids do not agree with this mechanism, nonsocorydine 7, resulting of an ortho-ortho coupling of reticuline followed by O-methylation and N-demethylation, and pallidine 10, made from the same precursor by aparapara coupling (13).…”

“…The crude alkaloids were extracted from the roots (75 kg) by previously described procedures (12). Extraction into organic solvents on the basis of differential basicity afforded a number of fractions.…”