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

Abstract

The synthesis of morphine (1) and pancratistatin (2) have been the subject of intense effort by the synthetic community for many years. Our focus on the total synthesis of these challenging targets resulted in several generations of approaches that combine enzymatic transformations with traditional synthetic protocols in order to provide for maximum efficiency and brevity in attaining the targets.Recombinant strains that express toluene dioxygenase (TDO) are used to provide the homochiral diene cis-diol derived from bromobenzene and containing the structural features of both ring C of morphine and ring C of pancratistatin. Bromocatechol, representing ring A of morphine, is also derived from bromobenzene by fermentation with E.coli JM109 that expresses TDO as well as catechol dehydrogenase. In this fashion twelve of the carbons in morphine originate in the same starting material. One approach is based on the Kazmaier-Claisen rearrangement of glycinate esters, the other on an intramolecular Heck reaction. The route to pancratistatin and to its unnatural analogs is based on the metal-mediated cyclotrimerization of acetylenic substrates of type 3. The core of this Amaryllidaceae constituent has been attained in the initial stages of this project. The details of the synthetic endeavours toward these and other heterocyclic targets will be disclosed with emphasis on practicality, brevity, and efficiency as guiding principles of enviromentally benign manufacturing of relevant compounds.

Asymmetric Synthesis of Isoquinoline Alkaloids: 2004–2015

“…Applying enantiomerically pure diols of type 986 , readily available from the corresponding aromatics by chemoenzymatic transformations, was reviewed by Hudlicky . A diversity of alkaloid’s structures have been constructed, e.g., of lycorine-, ,, crynine-, , montanine-, ,, as well as of pancratistatine-type natural and unnatural products.…”

Amaryllidaceae and Sceletium alkaloids

“…86 Arene dioxygenase enzyme-mediated biotransformations have produced a large variety of arene cis-dihydrodiol biometabolites from parent arenes, 87 which have proven to be valuable and versatile chiral building blocks for synthesis of complex natural products. 88 Taking advantage of enzyme-mediated dihydroxylation of halobenzene to generate cis-1,2-dihydrocatechol 148 as the starting material, several unnatural enantiomers of pancratistatin-type alkaloids, (+)-lycoricidine 149, 3-epi-lycoricidine 150, 4-deoxy-3-epi-lycoricidine 151 and narciclasine 62, have been concisely synthesized. 89,90 Using the same starting material 148, 7-deoxy-1-carboxaldehyde and two carboxylic acid derivatives 152a,b of pancratistatin 16 have been prepared by solvent-free intramolecular aziridine opening and phenanthreneto-phenanthridinone cyclization.…”

Amaryllidaceae and Sceletium alkaloids

“…Due to their antitumor activity, as well as their complicated stereochemistry, pancratistatin-type alkaloids have been an intriguing focus for synthetic chemists. 104, 105 A concise total synthesis of (+)-pancratistatin 14 has been completed from pinitol 188 by employing an arylcerium induced substitution reaction. 106 Cyclic sulfate 189 was treated with one equivalent of t-BuLi followed by addition of anhydrous CeCl 3 to effect the key nucleophilic substitution to give 190.…”