Comparison of Approaches to ent-Morphine via Radical, Cationic, and Heck-Type Cyclizations

Abstract

Dedicated to Professor Otakar Červinka on the occasion of his 75th birthday.3-(2-{6S-(2-Bromo-6-methoxyphenoxy)-5S-[tert-butyl(dimethyl)silyloxy)cyclohex-1-en-1-yl}-ethyl)oxazol-2(3H)-one 14 was subjected to Heck cyclization conditions to afford dibenzofuran derivative 16. The comparison of stepwise vs cascade approaches to 8 via radical, cationic, and Heck-type cyclizations is discussed.We are continuing to focus our attention on devising an efficient synthesis of morphine (1) 1,2 . During the last eight years we have investigated several chemoenzymatic approaches, all based on the general plan described in Scheme 1. The disconnection shown is based on the anticipation that the absolute stereochemistry of ring C can be derived from diene diol 2, prepared by toluene dioxygenase-mediated biooxidation of β-halo arenes of type 3 (ref. 3 ). Since the pioneering work of Gibson, who elucidated the degradation pathway of arenes by the soil bacterium Pseudomonas putida 4 , efficient recombinant organisms for the transformation of 3 to 2 have become available 5 , as has a general procedure for the production of various metabolites 6 . In addition, the expression of catechol dehydrogenase, the enzyme for the second step of the degradation pathway, enables the conversion of bromobenzene (5), via its diene diol, to bromocatechol, which after methylation becomes our synthon (4) for morphine's aromatic A ring 7 .

The Quest for a Practical Synthesis of Morphine Alkaloids and Their Derivatives by Chemoenzymatic Methods

“…The radical cyclization of 40 produced isoquinoline 41 as the major product (2:1) with the ent -configuration of C-9. In contrast, isoquinoline 49 , with C-9 in the natural configuration, was the major product of an acyl-imminium closure of 48 , Scheme . The Heck closure of 50 yielded neopinone-type intermediate 51 in 57% yield.…”

The role of biocatalysis in the asymmetric synthesis of alkaloids

“… 85 An entry to the natural series of morphinan alkaloids was finally established by a Heck cyclisation approach ( Scheme 18c ), using the chemo-enzymatically prepared building blocks 148 and 153 . 86 A Heck-based enantiodivergent synthesis of both enantiomers of codeine ( 142 ), which uses mercury( ii )-catalysed hydroamination for closing ring D ( Scheme 18d ), has also been reported recently. 87 A further variation of this route has been employed in the synthesis of ent -neopinone ( ent - 42a ), in which the D ring is closed by a 1,6-conjugate addition of the amine to C9.…”

Chemoenzymatic synthesis of complex natural and unnatural products: morphine, pancratistatin, and their analogs

“…Morphine. Several approaches to this alkaloid have been pursued in the groups over the last 15 years and have been published [21][22][23][24][25][26] and reviewed. [1][2][3] In 1997 we reported an approach to morphine based on the recognition that the biphenyl-like compound 33 could be derived from the aminoacid 34 by combination of Suzuki coupling and Kazmaier-Claisen rearrangement of glycinate enter 36 to acid 35 as shown in Scheme 7.…”