Natural Products with Anti‐Bredt and Bridgehead Double Bonds

Well over a hundred years ago, Professor Julius Bredt embarked on a career pursuing and critiquing bridged bicyclic systems that contained ring strain induced by the presence of a bridgehead olefin. These endeavors founded what we now know as Bredt’s rule (Bredtsche Regel). Physical, theoretical, and synthetic organic chemists have intensely studied this premise, pushing the boundaries of such systems to arrive at a better understood physical phenomenon. Mother nature has also seen fit to construct molecules containing bridgehead double bonds that encompass Bredt’s rule. For the first time, this topic is reviewed in a natural product context.     

Stable Aziridinium Salts as Versatile Intermediates: Isolation and Regio‐ and Stereoselective Ring‐Opening and Rearrangement

Rock trapping and exploration : Aziridinium bromide salts were discovered serendipitously during bromination of N,N‐dicarboxymethylated β‐amino alcohols. Regiospecific ring‐opening and rearrangement of the isolated, surprisingly stable aziridinium salts produces useful molecules including C‐functionalized oxomorpholines and α,β‐unsaturated amines.

     

Air‐Stable Oxyallyl Patterns and a Switchable N‐Heterocyclic Carbene

Oxyallyl derivatives are typically elusive compounds. Even recently reported “stabilized” 1,3‐diaminooxyallyl species are still highly reactive and have short lifetimes at room temperature. Herein, we report the synthesis and preliminary study of mesoionic pyrimidine derivatives that feature 1,3‐bis(dimethylamino)oxyallyl patterns with an unprecedented level of stabilization. The latter are not only insensitive towards air and moisture, but they are also compatible with the formation of an ancillary stable N‐heterocyclic carbene moiety. As the oxyallyl pattern is proton‐responsive, it allows the reversible switching of the electronic properties of the carbene, as a ligand.     

Catalytic Enantioselective Cloke–Wilson Rearrangement

Racemic cyclopropyl ketones undergo enantioselective rearrangement to deliver the corresponding dihydrofurans in the presence of a chiral phosphoric acid as the catalyst. The reaction involves activation of the donor‐acceptor cyclopropane substrate by the chiral Brønsted acid catalyst to promote the ring‐opening event, thus generating a carbocationic intermediate that subsequently undergoes cyclization. Computational studies and control experiments support this mechanistic pathway.     

Tetrahedrane--dossier of an unknown

To probe whether tetrahedrane should be isolable the thermodynamics and kinetics of C4H4 singlet and triplet structures were studied extensively at the CCSD(T)/cc-pVTZ//CCSD(T)/cc-pVDZ, CCSD(T)/cc-pVDZ, CCSD(T)/cc-pVDZ//B3 LYP/6-311G**, and B3 LYP/6-311G** levels of theory. The reaction of cyclopropene with atomic carbon, which was previously suggested to involve tetrahedrane as a reactive intermediate, was re-examined experimentally with low-temperature matrix-isolation techniques. While experimental and theoretical results exclude the intermediacy of tetrahedrane in the above reaction, it is predicted to be an isolable molecule. Among the many C4H4 species, we pay special attention to the electronic effects on the ground state multiplicity of the respective carbenes.     

Ion Pairing and Salt Structure in Organic Salts through Diffusion,Overhauser, DFT and X‐ray Methods

Pulsed gradient spin‐echo (PGSE) diffusion characteristics for a) the new [brucinium][X] salts 6 a – f [ a : X=BF₄^?; b : X=PF₆^?; c : X=MeSO₃^?, d : X=CF₃SO₃^?; e : X=BArF^?; f : X=PtCl₃(C₂H₄)^?], b) 4‐tert‐butyl‐N‐benzyl analogue, 7 and c) the aryl carbocations (p‐R‐C₆H₄)₂CH 9 a (R=CH₃O) and 9 b (R=(CH₃)₂N), (p‐CH₃O‐C₆H₄)_xCPh_3?x⁺ 10 a – c (x=1–3, respectively) and (p‐R‐C₆H₄)₃C⁺ 11 (R=(CH₃)₂N) and 12 (R=H) all in several different solvents, are reported. The solvent dependence suggests strong ion pairing in CDCl₃, intermediate ion pairing in CD₂Cl₂ and little ion pairing in [D₆]acetone. ¹H, ¹⁹F HOESY NMR spectra (HOESY: heteronuclear Overhauser effect spectroscopy) for 6 and 7 reveal a specific approach of the anion with respect to the brucinium cation plus subtle changes, which are related to the anion itself. Further, for carbocations 9 – 12 , (all as BF₄^? salts) based on the NOE results, one finds marked changes in the relative positions of the BF₄^? anion. In these aryl cationic species the anion can be located either a) very close to the carbonium ion carbon b) in an intermediate position or c) proximate to the N or O atom of the p‐substituent and remote from the formally positive C atom. This represents the first example of such a positional dependence of an anion on the structure of the carbocation. DFT calculations support the experimental HOESY results. The solid‐state structures for 6 c and the novel Zeise's salt derivative, [brucinium][PtCl₃(C₂H₄)], 6 f , are reported. Analysis of ¹⁹⁵Pt NMR and other NMR measurements suggest that the η²‐C₂H₄ bonding to the platinum centre in 6 f is very similar to that found in K[PtCl₃(C₂H₄)]. Field dependent T₁ measurements on [brucinium][PtCl₃(C₂H₄)] and K[PtCl₃(C₂H₄)], are reported and suggested to be useful in recognizing aggregation effects.     

8,14,30,36‐Tetramethoxy[2.0.2.0](1,6)naphthalenophane‐1,19‐diyne: A Double‐Helically Twisted Cyclophane by Diastereoselective Dimerization

The title compound and its corresponding etheno‐ and ethano‐bridged compounds were successfully synthesized in enantiomerically pure form by McMurry coupling of 2,2′‐dimethoxy‐(R)‐ or ‐(S)‐1,1′‐binaphthyl‐6,6′‐dicarbaldehydes as the key reaction. The reaction proceeded in a highly diastereoselective manner; the reaction of the racemic dialdehyde did not afford the meso coupling product but gave only the racemic one in poor yield. The diyne crystallized in the chiral monoclinic space group P2₁ from toluene/hexane. Structural analysis reveals that it has a considerably twisted double‐helical structure in crystal form. The spectral properties (NMR, UV/Vis, and CD) clearly indicate the highly strained nature of the molecule. In particular, its UV/Vis and CD spectra exhibit a bathochromic shift of about 20 nm for the naphthyl π–π* transitions.     

High Reactivity of Strained Seven‐Membered‐Ring trans‐Alkenes

trans‐Oxasilacycloheptenes are highly reactive strained alkenes. Competition reactions showed that these seven‐membered ring trans‐alkenes underwent [4+2] cycloaddition reactions faster than a trans‐cyclooctene. They also reacted with quinones and dimethyl acetylenedicarboxylate to form adducts with high diastereoselectivity. Kinetic studies showed that ring strain increases nucleophilicity by approximately 10⁹.     

Synthesis and Ligand Properties of a Persistent,All‐Carbon Four‐Membered‐Ring Allene

A single donor substituent at each terminus is sufficient to make the CCC skeleton of allenes very flexible and give carbon(0) character to the central carbon atom. This allows the synthesis of a four‐membered carbocyclic allene, which can be doubly protonated and behaves as a very strong η¹‐donor ligand for transition metals (see scheme).

     

N‐Heterocyclic‐Carbene‐Catalyzed Synthesis of 2‐Aryl Indoles

A convergent and efficient transition‐metal‐free catalytic synthesis of 2‐aryl‐indoles has been developed. The interception of a highly reactive and transient aza‐ortho‐quinone methide by an acyl anion equivalent generated through N‐hetereocyclic carbene catalysis is central to this successful strategy. High yields and a wide scope as well as the streamlined synthesis of a kinase inhibitor are reported.     

Gold(I)‐Catalysed Cycloisomerisation of 1,6‐Cyclopropene‐enes

The gold(I)‐catalysed cycloisomerisation of appropriately substituted 1,6‐cyclopropene‐enes proceeds through regioselective electrophilic ring opening of the three‐membered ring to generate an alkenyl gold carbenoid that achieves the intramolecular cyclopropanation of the remote olefin. This strategy allows straightforward, highly efficient and diastereoselective access to a variety of substituted 3‐oxa‐ and 3‐azabicyclo[4.1.0]heptanes, as well as to bicyclo[4.1.0]heptan‐3‐ol derivatives. Since the isopropylidene group in the resulting cycloisomerisation products can be subjected to ozonolysis, 3,3‐dimethylcyclopropenes behave as interesting surrogates for α‐diazoketones.     

Strain‐Accelerated Formation of Chiral,Optically Active Buta‐1,3‐dienes

The formal [2+2] cycloaddition–retroelectrocyclization (CA–RE) reactions between tetracyanoethylene (TCNE) and strained, electron‐rich dibenzo‐fused cyclooctynes were studied. The effect of ring strain on the reaction kinetics was quantified, revealing that the rates of cycloaddition using strained, cyclic alkynes are up to 5500 times greater at 298 K than those of reactions using unstrained alkynes. Cyclobutene reaction intermediates, as well as buta‐1,3‐diene products, were isolated and their structures were studied crystallographically. Isolation of a rare example of a chiral buta‐1,3‐diene that is optically active and configurationally stable at room temperature is reported. Computational studies on the enantiomerization pathway of the buta‐1,3‐diene products showed that the eight‐membered ring inverts via a boat conformer in a ring‐flip mechanism. In agreement with computed values, experimentally measured activation barriers of racemization in these compounds were found to be up to 26 kcal mol^?1.     

Philicity of Acetonyl and Benzoyl Radicals: A Comparative Experimental and Computational Study

In this work, the reactivities of acetonyl and benzoyl radicals in aromatic substitution and addition reactions have been compared in an experimental and computational study. The results show that acetonyl is more electrophilic than benzoyl, which is rather nucleophilic. A Hammett plot analysis of the addition reactions of the two radicals to substituted styrenes clearly support the nucleophilicity of benzoyl, but in the case of acetonyl, no satisfactory linear correlation with a single substituent-related parameter was found. Computational calculations helped to rationalize this effect, and a good linear correlation was found with a combination of polar parameters (σ⁺) and the radical stabilization energies of the formed intermediates. Based on the calculated philicity indices for benzoyl and acetonyl, a quantitative comparison of these two radicals with many other reported radicals is possible, which may help to predict the reactivities of other aromatic radical substitution reactions.     

Structure and Reactivity of an Isolable Seven‐Membered‐Ring trans‐Alkene

The isolation and characterization of a trans‐oxasilacycloheptene is reported. Single‐crystal X‐ray crystallographic studies indicate a high level of strain and deviation from ideal geometry. Reactions with several electrophiles demonstrated the nucleophilicity of the C?C double bond, affording oxasilacycloheptane and tetrahydrofuran products as single diastereomers.