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Current Applications of Suzuki–Miyaura Coupling Reaction in The Total Synthesis of Natural Products: An update

Conjugate (or 1,4-) additions of carbanionic species to α,β-unsaturated carbonyl compounds are vital to research in organic and medicinal chemistry, and there are several chiral catalysts that facilitate the catalytic enantioselective additions of nucleophiles to enoates. Nonetheless, catalytic enantioselective 1,6-conjugate additions are uncommon, and ones that incorporate readily functionalizable moieties, such as propargyl or allyl groups, into acyclic α,β,γ,δ-doubly unsaturated acceptors are unknown. Chemical transformations that could generate a new bond at the C6 position of a dienoate are particularly desirable because the resulting products could then be subjected to further modifications. However, such reactions, especially when dienoates contain two equally substituted olefins, are scarce and are confined to reactions promoted by a phosphine-copper catalyst (with an alkyl Grignard reagent, dialkylzinc or trialkylaluminium compounds), a diene-iridium catalyst (with arylboroxines), or a bisphosphine-cobalt catalyst (with monosilyl-acetylenes). 1,6-Conjugate additions are otherwise limited to substrates where there is full substitution at the C4 position. It is unclear why certain catalysts favour bond formation at C6, and-although there are a small number of catalytic enantioselective conjugate allyl additions-related 1,6-additions and processes involving a propargyl unit are non-existent. Here we show that an easily accessible organocopper catalyst can promote 1,6-conjugate additions of propargyl and 2-boryl-substituted allyl groups to acyclic dienoates with high selectivity. A commercially available allenyl-boron compound or a monosubstituted allene may be used. Products can be obtained in up to 83 per cent yield, >98:2 diastereomeric ratio (for allyl additions) and 99:1 enantiomeric ratio. We elucidate the mechanistic details, including the origins of high site selectivity (1,6- versus 1,4-) and enantioselectivity as a function of the catalyst structure and reaction type, by means of density functional theory calculations. The utility of the approach is highlighted by an application towards enantioselective synthesis of the anti-HIV agent (-)-equisetin.

Catalytic enantioselective 1,6-conjugate additions of propargyl and allyl groups

The metathesis reactions, in their various versions, have become a powerful and extremely valuable tool for the formation of carbon–carbon bonds in organic synthesis. The plethora of available catalysts to perform these reactions, combined with the various transformations that can be accomplished, have positioned the metathesis processes as one of the most important reactions of this century. In this review, we highlight the most relevant synthetic contributions published between 2012 and early 2018 in the field of total synthesis, reflecting the state of the art of this chemistry and demonstrating the significant synthetic potential of these methodologies. 1 	Introduction 2 	Alkene Metathesis in Total Synthesis 2.1 	Total Synthesis Based on a Ring-Closing-Metathesis Reaction 2.2 	Total Synthesis Based on a Cross-Metathesis Reaction 2.3 	Strategies for Selective and Efficient Metathesis Reactions of Alkenes 2.3.1 	Temporary Tethered Ring-Closing Metathesis 2.3.2 	Relay Ring-Closing Metathesis 2.3.3 	Stereoselective Alkene Metathesis 2.3.4 	Alkene Metathesis in Tandem Reactions 3 	Enyne Metathesis in Total Synthesis 3.1 	Total Syntheses Based on a Ring-Closing Enyne-Metathesis Reaction 3.2 	Total Syntheses Based on an Enyne Cross-Metathesis Reaction 3.3 	Enyne Metathesis in Tandem Reactions 4 	Alkyne Metathesis in Total Synthesis 4.1 	Total Synthesis Based on a Ring-Closing Alkyne-Metathesis Reaction 4.2 	Other Types of Alkyne-Metathesis Reactions 5 	Conclusions

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Recent Advances in Total Synthesis via Metathesis Reactions

The chiral oxazoline motif is present in many ligands that have been extensively applied in a series of important metal-catalyzed enantioselective reactions. This Review aims to provide a comprehensive overview of the most significant applications of oxazoline-containing ligands reported in the literature starting from 2009 until the end of 2018. The ligands are classified not by the reaction to which their metal complexes have been applied but by the nature of the denticity, chirality, and donor atoms involved. As a result, the continued development of ligand architectural design from mono(oxazolines), to bis(oxazolines), to tris(oxazolines) and tetra(oxazolines) and variations thereof can be more easily monitored by the reader. In addition, the key transition states of selected asymmetric transformations will be given to illustrate the features that give rise to high levels of asymmetric induction. As a further aid to the reader, we summarize the majority of schemes with representative examples that highlight the variation in % yields and % ees for carefully selected substrates. This Review should be of particular interest to the experts in the field but also serve as a useful starting point to new researchers in this area. It is hoped that this Review will stimulate both the development/design of new ligands and their applications in novel metal-catalyzed asymmetric transformations.

Further Developments and Applications of Oxazoline-Containing Ligands in Asymmetric Catalysis.

The first synthesis of (±)-tetrapetalone A-Me aglycon is described. Key bond-forming reactions include Nazarov cyclization, a ring-closing metathesis promoted with complete diastereoselectivity by a chiral molybdenum-based complex, tandem conjugate reduction/intramolecular aldol cyclization, and oxidative dearomatization.

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Synthesis of (±)‐Tetrapetalone A‐Me Aglycon

Total synthesis of (-)-ecklonialactone B.

The enantioselective synthesis of (−)-9,10-dihydroecklonialactone B is described. The catalytic asymmetric Claisen rearrangement of a Gosteli-type allyl vinyl ether was utilized to afford an acyclic α-keto ester building block endowed with functionality amenable to the preparation of the carbocyclic target molecule by suitable postrearrangement transformations: A highly diastereoselective Corey–Bakshi–Shibata reduction of a β-chiral α-keto ester and a reductive homologation of an α-hydroxy ester. A transprotection tactic by a chemoselective intramolecular 6-exo-trig iodoetherification enabled regioselective ring-closing alkene metatheses to afford the 5- as well as the 14-membered ring, however, with mixed success in terms of E/Z selectivity.

Catalytic asymmetric Claisen rearrangement of Gosteli-type allyl vinyl ethers: total synthesis of (-)-9,10-dihydroecklonialactone B.

Total Synthesis and Structural Assignment of Curvicollide C

89Zr represents a highly favorable positron emitter for application in immuno-PET (Positron Emission Tomography) imaging. Clinically, the 89Zr4+ ion is introduced into antibodies by complexation with desferrioxamine B. However, producing complexes of limited kinetic inertness. Therefore, several new chelators for 89Zr introduction have been developed over the last years. Of these, the direct comparison of the most relevant ones for clinical translation, DFO* and 3,4,3-(LI-1,2-HOPO), is still missing. Thus, we directly compared DFO with DFO* and 3,4,3-(LI-1,2-HOPO) immunoconjugates to identify the most suitable agent stable 89Zr-complexation. The chelators were introduced into cetuximab, and an optical analysis method was developed, enabling the efficient quantification of derivatization sites per protein. The cetuximab conjugates were efficiently obtained and radiolabeled with 89Zr at 37 °C within 30 min, giving the [89Zr]Zr-cetuximab derivatives in high radiochemical yields and purities of >99% as well as specific activities of 50 MBq/mg. The immunoreactive fraction of all 89Zr-labeled cetuximab derivatives was determined to be in the range of 86.5–88.1%. In vivo PET imaging and ex vivo biodistribution studies in tumor-bearing animals revealed a comparable and significantly higher kinetic inertness for both [89Zr]Zr-3,4,3-(LI-1,2-HOPO)-cetuximab and [89Zr]Zr-DFO*-cetuximab, compared to [89Zr]Zr-DFO-cetuximab. Of these, [89Zr]Zr-DFO*-cetuximab showed a considerably more favorable pharmacokinetic profile with significantly lower liver and spleen retention than [89Zr]Zr-3,4,3-(LI-1,2-HOPO)-cetuximab. Since [89Zr]Zr-DFO* demonstrates a very high kinetic inertness, paired with a highly favorable pharmacokinetic profile of the resulting antibody conjugate, DFO* currently represents the most suitable chelator candidate for stable 89Zr-radiolabeling of antibodies and clinical translation.

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Toward Optimized 89Zr-Immuno-PET: Side-by-Side Comparison of [89Zr]Zr-DFO-, [89Zr]Zr-3,4,3-(LI-1,2-HOPO)- and [89Zr]Zr-DFO*-Cetuximab for Tumor Imaging: Which Chelator Is the Most Suitable?

https://journals.iucr.org/x/issues/2021/09/00/hb4390/hb4390.pdf

Valeska von Kiedrowski

Papers

Total synthesis of (-)-ecklonialactone B.

Catalytic asymmetric Claisen rearrangement of Gosteli-type allyl vinyl ethers: total synthesis of (-)-9,10-dihydroecklonialactone B.

Total Synthesis and Structural Assignment of Curvicollide C

Toward Optimized 89Zr-Immuno-PET: Side-by-Side Comparison of [89Zr]Zr-DFO-, [89Zr]Zr-3,4,3-(LI-1,2-HOPO)- and [89Zr]Zr-DFO*-Cetuximab for Tumor Imaging: Which Chelator Is the Most Suitable?

(2R,4S,5S)-5-Hydroxy-4-methyl-3-oxohept-6-en-2-yl benzoate

Valeska von Kiedrowski

Papers

Total synthesis of (-)-ecklonialactone B.

Catalytic asymmetric Claisen rearrangement of Gosteli-type allyl vinyl ethers: total synthesis of (-)-9,10-dihydroecklonialactone B.

Total Synthesis and Structural Assignment of Curvicollide C

Toward Optimized 89Zr-Immuno-PET: Side-by-Side Comparison of [89Zr]Zr-DFO-, [89Zr]Zr-3,4,3-(LI-1,2-HOPO)- and [89Zr]Zr-DFO*-Cetuximab for Tumor Imaging: Which Chelator Is the Most Suitable?

(2R,4S,5S)-5-Hy­droxy-4-methyl-3-oxohept-6-en-2-yl benzoate

(2R,4S,5S)-5-Hydroxy-4-methyl-3-oxohept-6-en-2-yl benzoate