Lars K. Hansen

Copper Corroles Are Inherently Saddled

X-ray crystallographic analyses of two sterically unhindered copper meso-triarylcorroles, Cu[5,15-P(2)-10-(4-MeOP)C] and Cu[5,15-(4-CF(3)P)(2)-10-(4-MeOP)C] (P = phenyl and C = corrole), revealed substantially saddled corrole rings. These results are in marked contrast to those on highly sterically hindered cobalt(III) and iridium(III) corroles, which exhibit planar corrole macrocycles. The solution to this conundrum is that copper corroles are inherently saddled, as a result of a specific copper(d)-corrole(pi) orbital interaction. This orbital interaction results in a noninnocent corrole ligand, and the overall electronic structure may thus be described as Cu(II)-corrole(*2-). While many specific metal(d)-macrocycle(pi) orbital interactions are known for nonplanar metalloporphyrins, this work provides a rare example of such an orbital interaction providing the actual driving force for a significant nonplanar distortion. Our findings on copper corroles, along with those of others on cobalt and iridium corroles, thus constitute an intriguing and somewhat counterintuitive chapter in the structural chemistry of metallocorroles.

Nonplanar, Noninnocent, and Chiral: A Strongly Saddled Metallocorrole

The first crystal structure of a copper beta-octabromo-meso-triarylcorrole exhibits a uniquely saddled corrole macrocycle, where adjacent pyrrole rings are tilted relative to each other by 60-80 degrees. Such strong nonplanarity may be contrasted with the essentially planar macrocycle conformations observed in the vast majority of metallocorrole crystal structures. Density functional theory calculations suggest that two effects, ligand noninnocence and peripheral overcrowding, acting in concert, are responsible for the unique, observed conformation.

Crystal structures of phosphate, iodide and iodate-inhibited phospholipase C from Bacillus cereus and structural investigations of the binding of reaction products and a substrate analogue

The crystal structure of the complex formed between phospholipase C (PLC) from Bacillus cereus and inorganic phosphate (Pi), which is an inhibitor, has been determined and refined to 2.1 A resolution. The final R-factor is 19.7%. We have also studied the binding of two other inhibitors, iodide and iodate, to PLC. X-ray data for these two complexes were collected to 2.8 A resolution during the search for heavy-atom derivatives. A series of screening experiments where PLC crystals have been treated with several reaction products and a substrate analogue were carried out to clarify the question of substrate binding. The results have so far been ambiguous but are discussed briefly. Phosphate and iodate are both found to bind to the three metal ions in the protein molecule, suggesting that these ions are involved directly in the catalytic process and thereby identifying the active site. PLC also binds nine iodide ions, eight of which are on the surface of the molecule and of lower occupancy. The ninth blocks the entrance to the active site cleft and is of higher occupancy. Altogether, these results suggest that the substrate, a phospholipid, is associated directly with the metal ions during catalysis.

Crystal structures of two furanosesquiterpenes from Commiphora sphaerocarpa

The relative stereochemistry of a furanosesquiterpene, reported previously from myrrh, but isolated here from Commiphora sphaerocarpa is determined for the first time as (1(10)E,2R*,4R*)-2-methoxy-8,12-epoxygermacra-1(10),7,11-trien-6-one. Likewise the stereochemistry of furanodienone was established by NMR and X-ray crystallography as (1(10)E,4E)-8,12-epoxygermacra-1(10),4,7,11-tetraen-6-one.

Asymmetric Diels–Alder reactions of N-sulfinyl dienophiles using chiral Ti(IV) Lewis acids

Abstract Enantioselective hetero Diels–Alder (HDA) reactions of 1,3-cyclohexadiene with benzyl N-sulfinylcarbamate 1a and with N-sulfinyl-p-toluensulfonamide 1b promoted by chiral Ti(IV)-based Lewis acids are reported. The obtained yields and enantiomeric excesses obtained are heavily dependant on the mode of catalyst preparation. Acceptable reproducibility was obtained with Ti(IV)-catalysts prepared from Me2TiCl2 and chiral diols. Testing of various chiral diols gave the endo adduct in yields of up to 69% with 76% ee. The absolute configuration of the HDA products were established by chemical correlation and verified by X-ray crystallography.

Two octanordammarane triterpenes from Commiphora kua

The resin of Commiphora kwo yielded two new octanordammarane triterpenes namely 15 alpha-hydroxymansumbinone and 28-acetoxy-15 alpha-hydroxymansumbinone, along with the four known compounds, mansumbinone, mansumbinol, (16S, 20R)-dihydroxydammar-24-en-3-one and T-cadinol. These structures were elucidated by spectroscopic techniques, including 1D and 2D NMR spectroscopy, and X-ray analysis.

Dihydroxyacetone dimers; solution and crystal structure of stereoisomers of 2,5-diethoxy-1,4-dioxane-2,5-dimethanol

Abstract 1,3-Dihydroxy-2-propanone (dihydroxyacetone) in aqueous solution is an equilibrium remeniscent of the one in ketoses. When reacted with triethyl orthoformate and ethanol two stable diethyl ethers were isolated and their structures have been shown to be the cis- and trans-isomers of 2,5-diethoxy-1,4-dioxane-2,5-dimethanol. NMR spectroscopy and X-ray crystallography revealed that the trans-isomer adapts chair conformation while the cis-isomer is a twist-boat both in solution and crystalline state.

Design of a Highly Selective and Potent Class of Non-planar Estrogen Receptor Agonists

Selective activation of the estrogen receptor β (ERβ) could be a safe approach to hormone replacement therapy for both women and men, in contrast to the estrogens currently used for women which activate both ERβ and ERα, occasionally causing severe side effects. The selective ERβ agonist AC‐131 has shown efficacy in animal models of Parkinson’s disease and neuropathic pain. With the use of AC‐131 as template, herein we report the discovery, synthesis, and structure–activity relationship (SAR) study of a new class of dihydrobenzofurans as potent and selective ERβ agonists. The SAR was established by enantioselective synthesis, molecular modeling, and whole‐cell‐based functional assays. The most potent diastereomer, cis‐10‐SR, was shown to have an EC50 value of <1 nM, potency 100‐fold higher than that of AC‐131. Even more interestingly, compound trans‐10‐SS exhibited 1000‐fold ERβ/ERα selectivity while still maintaining good potency (∼10 nM). In addition, trans‐10‐SS showed only partial agonist activity (30–60 % Eff.) toward ERα at 10 μM. This unprecedented selectivity could be rationalized by molecular modeling. Compound trans‐10‐SS appears to be the first molecule to take advantage of both conservative amino acid differences found in the α‐ and β‐faces of the binding cavities of ERα and ERβ.