Ping Lan

Chemoenzymatic Total Syntheses of Ribisins A, B, and D, Polyoxygenated Benzofuran Derivatives Displaying NGF-Potentiating Properties

Total syntheses of the structures, 1, 2, and 4, assigned to the biologically active natural products ribisins A, B, and D, respectively, have been achieved using the microbially derived and enantiomerically pure cis-1,2-dihydrocatechol 5 as starting material. Key steps include Suzuki-Miyaura cross-coupling, intramolecular Mitsunobu, and tandem epoxidation/rearrangement reactions. As a result of these studies, the structures of ribisins A and D have been confirmed while that of congener B was shown to be represented by 31 rather than 2.

Synthesis of a D-Ring Isomer of Galanthamine via a Radical-Based Smiles Rearrangement Reaction

The 1,9-ethanoiminomethano-bridged tetrahydrodibenzo[b,d]-furan 2, a non-natural isomer of the alkaloid (-)-galanthamine (1) varying in the manner in which the D-ring is annulated to the ABC-core, has been prepared in racemic form. The synthetic sequence starts with the cyclopropane 3 and involves intramolecular Heck alkenylation and radical-based Smiles rearrangement reactions as key steps. Unlike natural product 1, but as predicted by docking studies, compound 2 is not a potent inhibitor of acetylcholine esterase.

Chemoenzymatic synthesis of the enantiomer of 4,12-dihydroxysterpurene, the structure assigned to a metabolite isolated from the culture broth of Stereum purpureum.

Compound ent-1 has been prepared by engaging a derivative of the enantiomerically enriched and microbially derived cis-1,2-dihydrocatechol 6 in an intramolecular Diels-Alder reaction, elaboration of the adduct so-formed to the cyclopentannulated bicyclo[2.2.2]octenone 3, and photochemical rearrangement of this to the cyclobutanone 2. By such means it has been established that 4,12-dihydroxysterpurene (1) is not the structure of the natural product isolated by Xie and co-workers from a culture broth of Stereum purpureum.

Chemoenzymatic Total Syntheses of the Enantiomers of the Protoilludanes 8-Deoxydihydrotsugicoline and Radudiol.

Chemoenzymatic and stereoselective total syntheses of the non-natural enantiomeric forms of the recently isolated protoilludane natural products 8-deoxydihydrotsugicoline (1) and radudiol (2) (viz. ent-1 and ent-2, respectively) are reported. The key steps involve the Diels-Alder cycloaddition of cyclopent-2-en-1-one to the acetonide derived from enantiomerically pure and enzymatically derived cis-1,2-dihydrocatechol 3, elaboration of the resulting adduct to the tricyclic ketone 12, and a photochemically promoted rearrangement of this last compound to the octahydro-1H-cyclobuta[e]indenone 13.

Chemoenzymatic Synthesis of (+)-Asperpentyn and the Enantiomer of the Structure Assigned to Aspergillusol A

Total syntheses of (+)-asperpentyn (1) and compound ent-2, the enantiomer of the structure, 2, assigned to the natural product aspergillusol A are reported. Both reaction sequences employ the enzymatically derived and enantiomerically pure cis-1,2-dihydrocatechol 4 as starting material and use Sonogashira cross-coupling chemistry to install the required enyne side-chain. The (1)H and (13)C NMR spectroscopic data derived from compound ent-2 match those reported for aspergillusol A, thus suggesting that the gross structure of this natural product has been assigned correctly, although its absolute stereochemistry remains unclear.

The Palladium-Catalysed Intramolecular Alder-ene (IMAE) Reactions of Certain Heteroatom-Linked 1,6-Enynes: The Formation of Hexahydro-Indoles and -Benzofurans

A short review of the literature on palladium-catalysed intramolecular Alder-ene reactions of C-, N-, and O-linked 1,6-enynes is provided with a particular focus on the use of the latter two processes in the authors’ laboratories for the purposes of constructing various alkaloids.

Chemoenzymatic total synthesis and reassignment of the absolute configuration of ribisin C.

The enantiomerically pure and enzymatically derived cis-1,2-dihydrocatechol 5 has been converted, by two related pathways, into compounds 3 and ent-3. As a result, it has been determined that the true structure of the natural product ribisin C is represented by ent-3.

Devising New Syntheses of the Alkaloid Galanthamine, a Potent and Clinically Deployed Inhibitor of Acetylcholine Esterase

Abstract The alkaloid (−)-galanthamine ( 1 ), a potent inhibitor of acetylcholinesterase (AChE), is used clinically for the symptomatic treatment of mild to moderate forms of Alzheimers disease. The clinical demand for (−)-galanthamine together with the erosion of habitat of at least some of the source plants has created supply issues that have prompted numerous synthetic studies. Four distinct approaches for the assembly of the tetracyclic framework of compound 1 developed in the authors’ laboratories are described here. Two of these exploit an enantiomerically pure metabolite produced through the whole-cell dihydroxylation of bromobenzene as a precursor to the A-ring of natural product 1 . The second of these rapidly provides enantiomerically pure compounds that molecular docking studies suggest should be strong inhibitors of AChE. A third synthesis of (−)-galanthamine involving the de novo assembly of the aromatic C-ring is also described, as is a failed radical cyclization-based approach.

New, Homochiral Synthons Obtained through Simple Manipulations of Enzymatically Derived 3-Halo-cis-1,2-dihydrocatechols

The bromoepoxide 5a, which is obtained from the homochiral and enzymatically derived cis-1,2-dihydrocatechol 1a, is readily and efficiently transformed into either isomer 8a or the corresponding methoxymethyl-ether 2a. Though both of these products can be fully characterized, they are somewhat unstable, with the former being converted into the crystalline enone 3a on standing and the latter readily participating in a Diels–Alder cycloaddition reaction with the potent dienophile N-phenyl-1,2,4-triazoline-3,5-dione to give adduct 7a. The single-crystal X-ray structures of compounds 3a and 7a are reported. Using the related chemistry the chloro-analogue, 3b, of enone 3a can be obtained.

Syntheses of Gibberellins A15 and A24, the Key Metabolites in Gibberellin Biosynthesis

Gibberellins (GAs) are essential phytohormones involved in numerous aspects of plant growth and development. Notably, the biochemistry and genetics of GA biosynthesis, which is associated with their endogenous regulation, have been largely resolved; however, a crucial unsolved question remains: the precise mechanism of the stepwise oxidation and subsequent removal of C-20 from C20 precursors, leading to bioactive C19 gibberellins, is still unresolved. To satisfy numerous requests from biologists, practical preparations of certain GAs that were isolated in miniscule quantities are highly demanded. Herein, we report the first practical syntheses of GA15 and GA24, the key C20 metabolites in gibberellin biosynthesis, from commercially available GA3. The protocols are robust and offer the capacity to produce GA24 and GA15 under gram scales in high overall yields and thus aid in further biological and related studies.