Convergent total synthesis of (+)-calcipotriol: A scalable, modular approach to vitamin D analogs.

A convergent approach for the total synthesis of calcipotriol (brand name: Dovonex), a proven vitamin D analog used for the treatment of psoriasis, and medicinally relevant synthetic analogs is described. A complete approach, not wedded to semisynthesis, toward both the A-ring and CD-ring is reported. From a retrosynthetic standpoint, hidden symmetry within the decorated A-ring is disclosed, which allowed for scalable quantities of this advanced intermediate. In addition, a radical retrosynthetic approach is described, which highlights an electrochemical reductive coupling as well as an intramolecular hydrogen atom transfer Giese addition to establish the 6,5-transcarbon skeleton found in the vitamin D family. Finally, a late-stage decarboxylative cross-coupling approach allowed for the facile preparation of various C20-arylated derivatives that show promising biological activity in an initial bioassay.

Stereocontrolled Radical Thiophosphorylation.

The first practical, fully stereoselective P(V)-radical hydrophosphorylation is presented herein by using simple, limonene-derived reagent systems. A set of reagents have been developed that upon radical initiation react smoothly with olefins and other radical acceptors to generate P-chiral products, which can be further diversified (with conventional 2e- chemistry) to a range of underexplored bioisosteric building blocks. The reactions have a wide scope with excellent chemoselectivity, and the unexpected stereochemical outcome has been supported computationally and experimentally. Initial ADME studies are suggestive of the promising properties of this rarely explored chemical space.

Polarity-Reversal Strategy for the Functionalization of Electrophilic Strained Molecules via Light-Driven Cobalt Catalysis.

Strain-release-driven methodology is a powerful tool for accessing structural motifs, highly desirable by the pharmaceutical industry. The reactivity of spring-loaded cyclic reagents is dominated by transformations relying on their inherent electrophilic reactivity. Herein, we present a polarity-reversal strategy based on light-driven cobalt catalysis, which enables the generation of nucleophilic radicals through strain release. The applicability of this methodology is demonstrated by the design of two distinct types of reactions: Giese-type addition and Co/Ni-catalyzed cross-coupling. Moreover, a series of electrochemical, spectroscopic, and kinetic experiments as well as X-ray structural analysis of the intermediate alkylcobalt(III) complex give deeper insight into the mechanism of the reaction.

Vitamin B12 Catalysis: Probing the Structure/Efficacy Relationship.

Vitamin B12 is a cofactor for many enzymes, but it also functions as a catalyst in C-C bond-forming reactions. Herein, the impact of corrin structural modifications on their catalytic efficacy was examined. Derivatives with various substituents at c-, d-, and meso-positions were synthesised by using traditional and new microwave methodologies, and then tested in the model reaction of 1,1-diphenylethylene with ethyl diazoacetate. To complement the experimental data, cyclic voltammetry and DFT calculations were performed. Mainly alterations at the c- or d-positions influence both the reaction yield and selectivity.

Vitamin†B12 Phosphate Conjugation and Its Effect on Binding to the Human B12 -Binding Proteins Intrinsic Factor and Haptocorrin.

The binding of vitamin B12 derivatives to human B12 transporter proteins is strongly influenced by the type and site of modification of the cobalamin original structure. We have prepared the first cobalamin derivative modified at the phosphate moiety. The reaction conditions were fully optimized and its limitations examined. The resulting derivatives, particularly those bearing terminal alkyne and azide groups, were isolated and used in copper-catalyzed alkyne-azide cycloaddition reactions (CuAAC). Their sensitivity towards light revealed their potential as photocleavable molecules. The binding abilities of selected derivatives were examined and compared with cyanocobalamin. The interaction of the alkylated derivatives with haptocorrin was less affected than the interaction with intrinsic factor. Furthermore, the configuration of the phosphate moiety was irrelevant to the binding process.

Scalar relaxation of the second kind. A potential source of information on the dynamics of molecular movements. 4. Molecules with collinear C-H and C-Br bonds.

Continuing studies based on measurements of the nuclear spin relaxation rates running via the SC2 mechanism (scalar relaxation of the second kind), we present in this work the results obtained for three molecules: 9-bromotriptycene, 1,3,5-tribromobenzene, and 1-(2-bromoethynyl)-4-ethynylbenzene in which C-Br bond and one of C-H bonds are collinear. Separation of saturation-recovery or inversion-recovery curves of (13)C NMR signals of bromine-bonded carbons in the investigated compounds on two components has provided the longitudinal SC2 relaxation rates of these carbons in (79)Br- and (81)Br-containing isotopomers. These data have enabled experimental determination of the bromine-carbon spin-spin coupling constants and relaxation rates of quadrupole bromine nuclei, hardly accessible by direct measurements. At the same time the rotational diffusion parameters describing the reorientation of the C-Br vectors have been determined for the investigated molecules on the basis of the dipolar relaxation of protonated carbons. These diffusion parameters are crucial for interpretation of the bromine relaxation rates. The values of the indirect (1)J((13)C,(79)Br) coupling constants, magnetic shielding of carbon nuclei and quadrupole coupling constants of bromines, determined for the investigated compounds, have been compared with the results of the theoretical calculations which take into account relativistic effects. The origin of some divergences between the results obtained by different methods has been discussed.

Stereocontrolled access to thioisosteres of nucleoside di- and triphosphates.

Nucleoside diphosphates and triphosphates impact nearly every aspect of biochemistry; however, the use of such compounds as tools or medicinal leads for nucleotide-dependent enzymes and receptors is hampered by their rapid in vivo metabolism. Although a successful strategy to address the instability of the monophosphate moiety in oligonucleotide therapeutics has been accomplished by their isosteric replacement with phosphorothioates, no practical methods exist to rapidly and controllably access stereopure di- and triphosphate thioisosteres of both natural and unnatural nucleosides. Here we show how a modular, reagent-based platform can enable the stereocontrolled and scalable synthesis of a library of such molecules. This operationally simple approach provides access to pure stereoisomers of nucleoside α-thiodiphosphates and α-thiotriphosphates, as well as symmetrical or unsymmetrical dinucleoside thiodiphosphates and thiotriphosphates (including RNA cap reagents). We demonstrate that ligand-receptor interactions can be dramatically influenced by P-stereochemistry, showing that such thioisosteric replacements can have profound effects on the potency and stability of lead candidates.

Aryl versus Alkyl Redox-Active Diazoacetates ─ Light-Induced C-H Insertion or 1,2-Rearrangement.

Diazo compounds with redox-active leaving groups are versatile reagents for orthogonal functionalizations, previously utilized in the Rh-catalyzed synthesis of highly substituted cyclopropanes. Photochemical activation of aryl-substituted diazoacetates generates carbenes, whereas redox-active esters can furnish C-radicals via the photoexcitation of EDA complexes. However, the photochemical behavior of these two functionalities, while present in one molecule, remains to be defined. We demonstrate that under light irradiation, reactions occur only on the diazo moiety, leaving the NHPI functionality intact. Not only aryl- but also alkyl-substituted NHPI diazoacetates are activated by blue light; either C-H insertion or the hydrogen/carbon 1,2-rearrangement occurs depending on the aryl/alkyl group.

Reversal of regioselectivity in reactions of donor-acceptor cyclopropanes with electrophilic olefins.

Reactivity of donor-acceptor cyclopropanes towards nucleophiles and electrophiles is determined by the specific philicity of the carbon atoms originating from the strong polarization of the central C-C bond. Herein, we report that vitamin B12 catalysis enables the transformation of an initially electrophilic center into a nucleophilic radical that reacts with SOMOphiles. This radical-based strategy reverses the standard regioselectivity and thus complements the classical approaches.

Bioinspired Cobalt-Catalysis Enables Generation of Nucleophilic Radicals from Oxetanes.

Oxetanes are valuable building blocks due to their well-explored propensity to undergo ring-opening reactions with nucleophiles. However, their application as precursors of radical species is still elusive. Herein, we present a bioinspired cobalt-catalysis-based strategy to access unprecedented modes of radical reactivity via oxetane ring-opening. This powerful approach gives access to nucleophilic radicals that engage in reactions with SOMOphiles and low-valent transition metals. Importantly, the regioselectivity of these processes complements known methodologies.

Mild and Chemoselective Phosphorylation of Alcohols Using a Ψ-Reagent.

An operationally simple, scalable, and chemoselective method for the direct phosphorylation of alcohols using a P(V)-approach based on the Ψ-reagent platform is disclosed. The method features a broad substrate scope of utility in both simple and complex settings and provides access to valuable phosphorylated alcohols that would be otherwise difficult to obtain.