Ladderane Natural Products: From the Ground Up

The ladderane family of natural products are well known for their linearly concatenated cyclobutane skeletal structure. Owing to their unique carbocyclic framework, several chemical syntheses have been reported since their discovery in 2002. The focus of this review is to showcase the novel tactics that have been used to generate the ladderane core and the challenges that are associated with the synthesis of these unusual and complex natural products.     

Carbamoyl Radical‐Mediated Synthesis and Semipinacol Rearrangement of β‐Lactam Diols

In an approach to the biologically important 6‐azabicyclo[3.2.1]octane ring system, the scope of the tandem 4‐exo‐trig carbamoyl radical cyclization—dithiocarbamate group transfer reaction to ring‐fused β‐lactams is evaluated. β‐Lactams fused to five‐, six‐, and seven‐membered rings are prepared in good to excellent yield, and with moderate to complete control at the newly formed dithiocarbamate stereocentre. No cyclization is observed with an additional methyl substituent on the terminus of the double bond. Elimination of the dithiocarbamate group gives α,β‐ or β,γ‐unsaturated lactams depending on both the methodology employed (base‐mediated or thermal) and the nature of the carbocycle fused to the β‐lactam. Fused β‐lactam diols, obtained from catalytic OsO₄‐mediated dihydroxylation of α,β‐unsaturated β‐lactams, undergo semipinacol rearrangement via the corresponding cyclic sulfite or phosphorane to give keto‐bridged bicyclic amides by exclusive N‐acyl group migration. A monocyclic β‐lactam diol undergoes Appel reaction at a primary alcohol in preference to semipinacol rearrangement. Preliminary investigations into the chemo‐ and stereoselective manipulation of the two carbonyl groups present in a representative 7,8‐dioxo‐6‐azabicyclo[3.2.1]octane rearrangement product are also reported.     

Enantiomerically enriched cyclopropene derivatives: versatile building blocks in asymmetric synthesis

Enantiomerically enriched cyclopropene derivatives, the smallest possible unsaturated carbocycles, are of great synthetic interest since they serve as versatile reactive building blocks. Their reactivity results from the relief of the ring strain in the small molecule. They can be transformed into a wide variety of complex chiral structures and a special emphasis will be directed towards the preparation of enantiomerically enriched methylene- and alkylidenecyclopropane derivatives. The ready availability of a wide range of these chiral entities now provides an excellent opportunity to discover new and unique transformations that can further enrich mainstream synthetic methodology.     

Synthesis of Bicyclo[1.1.1]pentane Bioisosteres of Internal Alkynes and para‐Disubstituted Benzenes from [1.1.1]Propellane

We report a general preparation of arylated bicyclo[1.1.1]pentanes through the opening of [1.1.1]propellane with various arylmagnesium halides. After transmetalation with ZnCl₂ and Negishi cross‐coupling with aryl and heteroaryl halides, bis‐arylated bicyclo[1.1.1]pentanes are obtained. These bis‐arylated bicyclo[1.1.1]pentanes may be considered as bioisosteres of internal alkynes. Bioisosteres of tazarotene and the metabotropic glutamate receptor 5 (mGluR5) antagonist 2‐methyl‐6‐(phenylethynyl)pyridine were prepared and their physicochemical properties were evaluated.     

Synthesis and Structures of Polyphenylphenanthrenes

1,2,3,4,5,6,7,8-Octaphenylphenanthrene ( 4 ) and decaphenylphenanthrene ( 5 ) were prepared by very short syntheses (two or three steps) from tetraphenylfuran and polybrominated benzene derivatives. The X-ray structures of compounds 4 and 5 show them to be quite crowded, with the phenanthrene cores twisted by about 40° due to the clash of the C4 and C5 phenyl groups. Compound 4 was resolved by chromatography on a chiral support, and its free energy of activation for racemization was determined to be 24.6 kcal mol⁻¹ at 40 °C. Computational studies indicate that compound 5 has a racemization barrier approximately 6 kcal mol⁻¹ lower than 4 , and thus 5 would not be configurationally stable at room temperature.     

Intermolecular σ‐Bond Cross‐Exchange Reaction between Cyclopropenones and (Benzo)silacyclobutanes: Straightforward Access towards Sila(benzo)cycloheptenones

Described herein is the first intermolecular σ‐bond exchange reaction between the C?C bond of cyclopropenones and C?Si bond of (benzo)silacyclobutanes and it proceeds smoothly by treatment with either 1 mol % of a palladium or 2 mol % of a nickel catalyst. This reaction constitutes an unprecedented route for the synthesis of various sila(benzo)suberones. And it is also the first example of a σ‐bond exchange reaction involving cyclopropenones.     

Transformations of Strained Three-Membered Rings a Common,Yet Overlooked,Motif in Heavy-Atom Tunneling Reactions

Quantum mechanical tunneling has long been recognized as an important phenomenon when considering transformations dominated by a lightweight hydrogen atom. Tunneling of heavier atoms like carbon, initially dismissed as negligible, has seen a quickly increasing number of computationally predicted and/or experimentally confirmed examples over the last decade, thus highlighting its importance for a wide variety of reactions. However, no common structural motif has been pointed out within these seemingly unconnected examples, strongly limiting the predictability of the impact of heavy-atom tunneling on a given reaction. This Concept article will provide this perspective and showcase how the recognition of the formation and cleavage of three-membered rings as common motif can inform the prediction of and research into heavy-atom tunneling reactions.     

Ring Expansions of Boroles with Diazo Compounds: Steric Control of C or N Insertion and Aromatic/Nonaromatic Products

Access to novel imine‐substituted 1,2‐azaborinines, as well as highly arylated boracyclohexa‐3,5‐dienes has been developed by ring expansion of boroles with diazoalkanes with varying degrees of steric bulk. The formation of a diazoalkane intermediate is also discussed for the reaction of ortho‐brominated p‐tolyl‐azide with 1,2,3,4,5‐pentaphenylborole. Structural details as well as UV/Vis spectroscopic and cyclic voltammetric data are provided. These boron‐containing heterocycles have the potential to serve as building blocks for boron‐containing materials.     

Metal‐Free Ring‐Expansion Reaction of Six‐membered Sulfonylimines with Diazomethanes: An Approach toward Seven‐Membered Enesulfonamides

A new metal‐free, ring‐expansion reaction of six‐membered N‐sulfonylimines with unstable diazomethanes, generated in situ from the N‐tosylhydrazones, has been developed. This reaction delivers valuable seven‐membered enesulfonamides by a Tiffeneau–Demjanov rearrangement and intramolecular proton transfer tautomerization process. Moreover, this ring‐expansion reaction can be carried out in a one‐pot fashion and scaled up to the gram scale by using aryl aldehydes, without the need to isolate the N‐tosylhydrazone.     

An access to 3,4-(aminomethano)proline in racemic and enantiomerically pure form

Protected racemic and enantiomerically pure 3,4-(aminomethano)prolines rac-9 and (2S,2'R,3R,4R)-9 have been prepared applying a titanium-mediated reductive cyclopropanation as a key step. Thus, cyclopropanations of N,N-dibenzylformamide with titanacyclopropanes generated in situ from racemic or enantiomerically pure tert-butyl N-Boc-3,4-dehydroprolinates rac-8 or (S)-8 proceed diastereoselectively, and furnish the protected racemic and enantiomerically pure diamino acid 9. The latter was incorporated into three tripeptides containing glycyl, alanyl and phenylalanyl moieties.