Cornelia Wirtz

Mechanistic studies on a Cu-catalyzed aerobic oxidative coupling reaction with N-phenyl tetrahydroisoquinoline: structure of intermediates and the role of methanol as a solvent.

The mechanism of an aerobic copper-catalyzed oxidative coupling reaction with N-phenyl tetrahydroisoquinoline was investigated. The oxidized species formed from the reaction of the amine with the copper catalyst were analyzed by NMR-spectroscopy. An iminium dichlorocuprate was found to be the reactive intermediate and could be structurally characterized by X-ray crystallography. The effect of methanol to effectively stabilize the iminium ion was investigated and shown to be beneficial in an oxidative allylation reaction.

A Synthesis-Driven Structure Revision of Berkelic Acid Methyl Ester

Matrix metalloproteinases (MMPs) are a family of zinccontaining endopeptidases involved in homeostasis of the extracellular matrix. Abnormal activity of such enzymes is implicated in pathological processes that result in osteoarthritis, rheumathoid arthritis, and multiple sclerosis, and also plays a decisive role in tumor metastasis. Small-molecule inhibitors of the individual MMPs are therefore highly interesting as prospective complements to the current chemotherapeutic regimens used in clinical settings. A promising lead in this context is berkelic acid, which was isolated from a Penicillium species collected in the very hostile environment of Berkeley Pit Lake, a flooded former copper mine in Butte, Montana. This particular extremophile has adapted to the waters of this lake, which are highly acidic (pH 2.5) and contain a cocktail of heavy-metal salts in remarkably high concentrations. Bioassay-guided fractionation of the CHCl3 extracts of the fungus showed berkelic acid to be the major metabolite responsible for the pronounced inhibition of MMP-3 (GI50 = 1.87 mm). [3] Moreover, the compound exhibits selective and potent activity against the ovarian cancer cell line OVCAR-3 (GI50 = 91 nm). [3] As MMP-3 is upregulated in OVCAR-3 but not in other ovarian cancer cell lines, these preliminary activity and selectivity data are highly encouraging and suggest that berkelic acid and derivatives thereof deserve more intense scrutiny. 4] The remarkable structural attributes of berkelic acid add further to the appeal of this compound. It was assigned the constitution and relative configuration 1 (Scheme 1) mainly on the basis of NMR experiments. Recent model studies directed towards synthesizing berkelic acid appear to corroborate this proposed structure, even though they reached contradictory conclusions as to whether the acetalization that produces the conspicuous chromane spiroketal core is thermodynamically or kinetically controlled. We now report our own investigations on berkelic acid methyl ester (2) which not only resolve this open question but also suggest that the original structure assignment needs to be revised. Since the configuration at the lateral quaternary stereocenter C22 of berkelic acid is unknown, a convergent approach was adopted that should allow both possible isomers to be prepared by incorporating either enantiomer of synthon A at a late stage (Scheme 1). This route utilizes a Michael addition/spiroacetalization cascade intended to convert a linear precursor of type C into the tetracyclic core B of the target in one step. Compound C, in turn, should arise from an aldol condensation between the aromatic nucleus D and the polyketide segment E. The preparation of the required building block D (Scheme 2) commenced with the copper-catalyzed opening of (R)-(+)-2-pentyloxirane (> 99% ee) by the Grignard reagent derived from 3,5-bis(benzyloxy)-1-bromobenzene to give 3. Hydrogenolysis of the benzyl ethers followed by a regioselective Kolbe–Schmitt carboxylation of the resulting phenol 4 furnished acid 5, which was esterified by treatment with diazomethane prior to conversion into bis-TBS ether 8 by exhaustive silylation and selective mono-desilylation. Since the attempted direct formylation of this product was unrewarding, we chose to introduce the required formyl Scheme 1. Retrosynthetic analysis of the structure 1 attributed to berkelic acid.

Total Synthesis of Berkelic Acid

A productive total synthesis of both enantiomers of berkelic acid (1) is outlined that takes the structure revision of this bioactive fungal metabolite previously proposed by our group into account. The successful route relies on a fully optimized triple-deprotection/1,4-addition/spiroacetalization cascade reaction sequence, which delivers the tetracyclic core 32 of the target as a single isomer in excellent yield. The required cyclization precursor 31 is assembled from the polysubstituted benzaldehyde derivative 20 and methyl ketone 25 by an aldol condensation, in which the acetyl residue in 20 transforms from a passive protecting group into an active participant. Access to fragment 25 takes advantage of the Collum-Godenschwager variant of the ester enolate Claisen rearrangement, which clearly surpasses the classical Ireland-Claisen procedure in terms of diastereoselectivity. Although it is possible to elaborate 32 into the target without any additional manipulations of protecting groups, a short detour consisting in the conversion of the phenolic -OH into the corresponding TBS-ether is beneficial. It tempers the sensitivity of the compound toward oxidation and hence improves the efficiency and reliability of the final stages. Orthogonal ester groups for the benzoate and the aliphatic carboxylate terminus of the side chain secure an efficient liberation of free berkelic acid in the final step of the route.

A Two-Component Alkyne Metathesis Catalyst System with an Improved Substrate Scope and Functional Group Tolerance: Development and Applications to Natural Product Synthesis.

Although molybdenum alkylidyne complexes such as 1 endowed with triarylsilanolate ligands are excellent catalysts for alkyne metathesis, they can encounter limitations when (multiple) protic sites are present in a given substrate and/or when forcing conditions are necessary. In such cases, a catalyst formed in situ upon mixing of the trisamidomolybenum alkylidyne complex 3 and the readily available trisilanol derivatives 8 or 11 shows significantly better performance. This two-component system worked well for a series of model compounds comprising primary, secondary or phenolic -OH groups, as well as for a set of challenging (bis)propargylic substrates. Its remarkable efficiency is also evident from applications to the total syntheses of manshurolide, a highly strained sesquiterpene lactone with kinase inhibitory activity, and the structurally demanding immunosuppressive cyclodiyne ivorenolide A; in either case, the standard catalyst 1 largely failed to effect the critical macrocyclization, whereas the two-component system was fully operative. A study directed toward the quinolizidine alkaloid lythrancepine I features yet another instructive example, in that a triyne substrate was metathesized with the help of 3/11 such that two of the triple bonds participated in ring closure, while the third one passed uncompromised. As a spin-off of this project, a much improved ruthenium catalyst for the redox isomerization of propargyl alcohols to the corresponding enones was developed.

Polyunsaturated C‐Glycosidic 4‐Hydroxy‐2‐pyrone Derivatives: Total Synthesis Shows that Putative Orevactaene Is Likely Identical with Epipyrone A

Orevactaene and epipyrone A were previously thought to comprise the same polyunsaturated tail but notably different C-glycosylated 4-hydroxy-2-pyrone head groups. Total synthesis now shows that the signature bicyclic framework assigned to orevactaene is a chimera; the compound is almost certainly identical with epipyrone A, whose previously unknown stereochemistry has also been established during this study. Key to success was the ready formation of the bicyclic core of putative orevactaene by a sequence of two alkyne cycloisomerization reactions using tungsten and gold catalysis. Equally important was the flexibility in the assembly process gained by the use of heterobimetallic polyunsaturated modules whose termini could be selectively and consecutively addressed in a practical one-pot cross-coupling sequence.