Synthetic strategies for the ibophyllidine alkaloids.

Covering: 1975-2020The ibophyllidine alkaloids are unique pyrroloindole alkaloids exhibiting a five-membered D-ring in contrast to the six-membered D-ring of the more common Aspidosperma and Strychnos alkaloids. This structural feature has made them sought-after targets for organic chemists as well as for the elucidation of their biosynthesis. Beginning with the first and eponymous member ibophyllidine, isolation and structure determination is discussed. The main focus of this review are the diverse chemical approaches towards the ibophyllidines in context with their respective biosynthesis. The often employed Diels-Alder reaction strategy, two other named reaction-based strategies and the most recent enantioselective strategies are presented and compared.

Synthesis of Aspidodispermine via Pericyclic Framework Reconstruction.

A divergent approach to the pyrroloquinoline scaffold as present in the class of Aspidosperma alkaloids was developed. As a case study, abundant and renewable nicotinic acid was transformed via pericyclic framework reconstruction into aspidodispermine, a unique member of pyrroloquinoline alkaloids. The sequence comprises a [2 + 2]-photocycloaddition, a Ramberg-Bäcklund contraction, and a strain-promoted formal electrocyclic rearrangement of a bicyclo[2.2.0]hexene and is potentially extendable to pyrroloindole scaffolds as present in the ibophyllidine alkaloids.

Taxane Meets Propellane: First Chemical Synthesis of Highly Complex Diterpene Canataxpropellane.

The features of two iconic chemical classes are united in the structure of the highly complex diterpene canataxpropellane and set a daunting challenge that has been met by the Gaich group. Their daring strategy and its benefit to the field of terpene chemistry is presented and discussed in this Highlight.

Rearranged ergostane-type natural products: chemistry, biology, and medicinal aspects.

Classical steroids are long-known privileged leads in drug discovery. Their rearranged counterparts, though, have so far received less attention, although recent isolation and biological testing programmes have revealed a plethora of molecular entities that are both structurally intriguing, as well as biologically relevant. This review will highlight those natural products, and focus on ergostane-derived seco- and abeo-steroids. Their isolation, structure elucidation, and biological properties are reported. A special emphasis of this review lies in their respective (and typically proposed) biosyntheses, to help guide future bio-inspired synthetic attempts.

Relay Catalysis: Manganese(III) Phosphate Catalyzed Asymmetric Addition of ß-Dicarbonyls to ortho-Quinone Methides Generated by Catalytic Aerobic Oxidation.

The combination of an in situ formed MnL3 complex (HL = Hacac or R(C═O)CH2CO2R) and a chiral phosphoric acid HX* allows for a fully catalytic, asymmetric synthesis of 4H-chromenes starting from 2-alkyl-substituted phenols. The aerobic oxidation toward a transient ortho-quinone methide was efficiently catalyzed by a manganese(III) species MnL3 while the ensuing Michael addition of ß-dicarbonyl compounds proved to be catalyzed by a chiral manganese phosphate MnL2X*.

Identification of Fc Gamma Receptor Glycoforms That Produce Differential Binding Kinetics for Rituximab.

Fc gamma receptors (FcγR) bind the Fc region of antibodies and therefore play a prominent role in antibody-dependent cell-based immune responses such as ADCC, CDC and ADCP. The immune effector cell activity is directly linked to a productive molecular engagement of FcγRs where both the protein and glycan moiety of antibody and receptor can affect the interaction and in the present study we focus on the role of the FcγR glycans in this interaction. We provide a complete description of the glycan composition of Chinese hamster ovary (CHO) expressed human Fcγ receptors RI (CD64), RIIaArg131/His131 (CD32a), RIIb (CD32b) and RIIIaPhe158/Val158 (CD16a) and analyze the role of the glycans in the binding mechanism with IgG. The interactions of the monoclonal antibody rituximab with each FcγR were characterized and we discuss the CHO-FcγRIIIaPhe158/Val158 and CHO-FcγRI interactions and compare them to the equivalent interactions with human (HEK293) and murine (NS0) produced receptors. Our results reveal clear differences in the binding profiles of rituximab, which we attribute in each case to the differences in host cell-dependent FcγR glycosylation. The glycan profiles of CHO expressed FcγRI and FcγRIIIaPhe158/Val158 were compared with the glycan profiles of the receptors expressed in NS0 and HEK293 cells and we show that the glycan type and abundance differs significantly between the receptors and that these glycan differences lead to the observed differences in the respective FcγR binding patterns with rituximab. Oligomannose structures are prevalent on FcγRI from each source and likely contribute to the high affinity rituximab interaction through a stabilization effect. On FcγRI and FcγRIIIa large and sialylated glycans have a negative impact on rituximab binding, likely through destabilization of the interaction. In conclusion, the data show that the IgG1-FcγR binding kinetics differ depending on the glycosylation of the FcγR and further support a stabilizing role of FcγR glycans in the antibody binding interaction.