Bridgehead Substitution Research Articles

The Total Synthesis of Hyperfirin via a Cyclooctadiene Strategy.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) combine compelling structural complexity with effective biological activity. The total synthesis of Hyperfirin is reported as one linear sequence. Key to this novel modular strategy is to access the bicyclo[3.3.1]nonane-2,4,9-trione framework via transannular acylation of a decorated eight-membered ring, followed by late stage bridgehead substitution. The described route adds flexibility to PPAP construction and broadens the scope of eight-membered ring chemistry.

Functionalizations of Diamantane Dimers

Aim. To develop preparative methods for functionalization of diamantane dimers. Results and discussion. The reaction of 1,1′-bisdiamantane with bromine and the subsequent hydrolysis gives 6-hydroxy-1,1′-bіsdіamantane with a yield of 56 %. The reactions of 4,4′-bisdiamantane with nitric acid or liquid bromine followed by hydrolysis leads to a mixture of hydroxy derivatives and 1,1′-dihydroxy-4,4′-bisdiamantane after isomerization in sulfuric acid (with a yield of 73 %). Thus, the reactivity of bisdiamantanes with electrophiles is determined by the higher stability of the carbocations in the medial positions of the cages as shown by DFT computations. Whereas medial bridgehead substitutions dominate in reactions of 4,4′-bisdiamantane with elec­trophiles, the arylation with benzene in the presence of tert-butyl bromide and aluminum chloride gives bis-apical derivative – 9,9’-diphenyl-4,4’-bisdiamantane. Experimental part. The structure of 6-hydroxy-1,1′-bіsdіamantane was confirmed by X-ray diffraction analysis. The substitution pattern in 1,1′-dihydroxy-4,4′-bisdamantane was confirmed by 2D-NMR spectra. The arylation of 4,4′-bisdiamantane with benzene proceeds as bis-apical substitution to give highly symmetric 9,9’-di­phenyl-4,4’-bisdiamantane in 47 %. Conclusions. It has been shown that the medial bridgehead substitution dominates in the reactions of bisdia­mantanes with strong electrophiles, and only the arylation of 4,4′-bisdiamantane proceeds as a bis-apical substitution.Received: 31.03.2020Revised: 05.05.2020Accepted: 29.05.2020

Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition

LRH-1 is a nuclear receptor that regulates lipid metabolism and homeostasis, making it an attractive target for the treatment of diabetes and non-alcoholic fatty liver disease. Building on recent structural information about ligand binding from our labs, we have designed a series of new LRH-1 agonists that further engage LRH-1 through added polar interactions. While the current synthetic approach to this scaffold has, in large part, allowed for decoration of the agonist core, significant variation of the bridgehead substituent is mechanistically precluded. We have developed a new synthetic approach to overcome this limitation, identified that bridgehead substitution is necessary for LRH-1 activation, and described an alternative class of bridgehead substituents for effective LRH-1 agonist development. We determined the crystal structure of LRH-1 bound to a bridgehead-modified compound, revealing a promising opportunity to target novel regions of the ligand binding pocket to alter LRH-1 target gene expression.

Application of C-Terminal 7-Azabicyclo[2.2.1]heptane to Stabilize β-Strand-like Extended Conformation of a Neighboring α-Amino Acid.

β-Strands are formed by extended linear peptide chains that are usually paired to form β-sheet structure through interstrand hydrogen bonding. Linking a structured organic molecule with α-amino acid(s) can enforce or stabilize β-strand-like extended structures of the jointed amino acids. Spectroscopic and simulation studies indicated that the presence of a C-terminal 7-azabicyclo[2.2.1]heptane amine (Abh) favors a β-strand-like extended conformation of the adjacent α-amino acid on the N side. The bridgehead substitution of the Abh unit biases the amide cis-trans equilibrium of the adjacent α-amino acid residue to cis conformation. The proximity, specified by the presence of bond paths (such as H-H bond path) between the bridgehead proton of Abh and the α-proton of the α-amino acid provides a driving force favoring the extended conformation, which is independent of solvents. These results provide a basis for de novo design of β-strand-mimicking extended peptides by using β-strand enforcer/stabilizer even in the absence of the interstrand hydrogen bonding.

Effect of bridgehead substitution in the Grob fragmentation of norbornyl ketones: a new route to substituted halophenols.

Grob fragmentation of suitably designed bicyclic species often generates novel organic skeletons in a facile manner. Herein, we report a comprehensive account of an effective acid-catalyzed Grob fragmentation of trihalonorbornyl ketones to dihalophenol derivatives in good yields. The transformation entails tri-n-butyltin hydride (TBTH) mediated regioselective reduction of one of the two bridgehead halogens of readily available Diels-Alder adducts resulting from 1,2,3,4-tetrahalo-5,5-dimethoxycyclopentadiene and vinyl acetate derivatives, followed by its conversion to substituted halophenol species via a three-step hydrolysis-oxidation-rearrangement/aromatization strategy. Both alkyl and aryl substituted norbornyl ketones were studied. A detailed mechanistic analysis employing an isotope labeling experiment revealed plausible mechanistic pathways. Among the two bridgehead substituents, when halogen (X = Cl, Br) stays at C-1 and hydrogen (H, or deuterium, D) at C-4, then product formation takes place via exclusive protonation (supplied by an external acid) at β carbon (i.e. C-1) of a dienol moiety formed in situ during the Grob-fragmentation, followed by the removal of acidic 4-H (or 4-D) and halide ion (X(-)) from the resulting cyclohexenone intermediate prior to nucleophilic attack on the oxocarbenium ion by X(-) and final enolisation of cyclohexadienone species. A sharp deviation was observed with the regioisomeric bicyclic ketone, wherein the 4-X triggers a facile removal of X(-) and forms the end products without necessitating the involvement of the C-1 substituent (i.e. 1-H/D), thereby retaining it in the final halophenols. It clearly demonstrates how the bridgehead substituents in the two regioisomeric trihalo-norbornyl ketones steer the bicyclic systems to follow entirely different reaction pathways thus suggesting their crucial yet distinct roles in the overall reaction. The present transformation thus manifests the relevance of bridgehead substituents in the Grob fragmentation of such norbornyl systems. Our current strategy also allows one to access ortho-deuterated halophenol compounds.

ChemInform Abstract: Asymmetric Transformations by Deprotonation Using Chiral Lithium Amides

AbstractReview: 392 refs.

ChemInform Abstract: Adventures in Bridgehead Substitution Chemistry: Synthesis of Polycyclic Polyprenylated Acylphloroglucinols (PPAPs)

AbstractReview: 41 refs.

Impact of Regiochemistry and Isoelectronic Bridgehead Substitution on the Molecular Shape and Bulk Organization of Narrow Bandgap Chromophores

A comparison of two classes of small molecules relevant to the field of organic electronics is carried out at the molecular and supramolecular levels. First, two molecules that differ only in the position of a pyridyl N-atom within an acceptor fragment are compared and contrasted. X-ray investigation of single crystals reveals that positioning the pyridyl N-atoms proximal to the molecules center changes the molecular shape by bending the molecule into a banana shape. Second, we demonstrate that the banana shape of the molecule can be controlled by replacing a Si atom within the dithienosilole fragment with a C or Ge atom. Here, utilization of cyclopentadithiophene or dithienogermole as the internal electron-rich unit leads to a decrease or an increase in the bending of the conjugated backbone, respectively. Such molecular shape changes alter intermolecular packing and thus affect bulk properties, leading to large differences in the optical, thermal, and crystallization properties.

Bridgehead enolate or bridgehead organolithium? DFT calculations provide insights into a difficult bridgehead substitution reaction in the synthesis of the polycyclic polyprenylated acylphloroglucinol (PPAP) nemorosone

A computational study (B3LYP), of the metallation of a bridged ketone, an important step in the synthesis of a polycyclic polyprenylated acylphloroglucinol (PPAP), nemorosone, shows three energetically distinct structural possibilities for the lithiated intermediate. These findings, along with observations of the reactivity of the intermediates in bridgehead substitutions, suggest that different intermediates may be formed depending upon the type of process used for lithiation.

Adventures in bridgehead substitution chemistry: synthesis of polycyclic polyprenylated acylphloroglucinols (PPAPs)

The polycyclic polyprenylated acylphloroglucinol (PPAP) family of natural products includes important compounds with notable biological activities, such as garsubellin A, hyperforin and clusianone. The synthesis of these complex, bridged, highly oxidized and substituted systems presents a formidable challenge to synthetic chemists. This feature article describes how the use of unconventional bridgehead substitution chemistry has enabled the synthesis of these natural products and their analogues.

Synthesis of New Bridgehead Substituted Azabicyclo-[2.2.1]heptane and -[3.3.1]nonane Derivatives as Potent and Selective α7 Nicotinic Ligands

New azabicyclo[2.2.1]heptane and -[3.3.1]nonane derivatives containing a pyridinyl substituent at the bridgehead position have been synthesized via an efficient ten chemical steps pathway. Both chemical series were then evaluated in vitro for their affinity at α7 nicotinic receptors revealing nanomolar potency with notably excellent selectivity over the α4β2 nicotinic subtype.

Water-Stable Helical Structure of Tertiary Amides of Bicyclic β-Amino Acid Bearing 7-Azabicyclo[2.2.1]heptane. Full Control of Amide Cis−Trans Equilibrium by Bridgehead Substitution

Helical structures of oligomers of non-natural β-amino acids are significantly stabilized by intramolecular hydrogen bonding between main-chain amide moieties in many cases, but the structures are generally susceptible to the environment; that is, helices may unfold in protic solvents such as water. For the generation of non-hydrogen-bonded ordered structures of amides (tertiary amides in most cases), control of cis-trans isomerization is crucial, even though there is only a small sterical difference with respect to cis and trans orientations. We have established methods for synthesis of conformationally constrained β-proline mimics, that is, bridgehead-substituted 7-azabicyclo[2.2.1]heptane-2-endo-carboxylic acids. Our crystallographic, 1D- and 2D-NMR, and CD spectroscopic studies in solution revealed that a bridgehead methoxymethyl substituent completely biased the cis-trans equilibrium to the cis-amide structure along the main chain, and helical structures based on the cis-amide linkage were generated independently of the number of residues, from the minimalist dimer through the tetramer, hexamer, and up to the octamer, and irrespective of the solvent (e.g., water, alcohol, halogenated solvents, and cyclohexane). Generality of the control of the amide equilibrium by bridgehead substitution was also examined.

ChemInform Abstract: Synthesis of Doubly Bridgehead Substituted Bicyclo(1.1.1)pentanes. Radical Transformations of Bridgehead Halides and Carboxylic Acids.

Synthetic transformations of the 1-bicyclo [1.1.1] pentyl bridgehead radicals generated from corresponding bridgehead iodides and carboxylic acids are described. The relatively high nucleophilicity of these radicals was utilized in reactions with carbonyl compounds

Synthesis of Nemorosone via a Difficult Bridgehead Substitution Reaction

The synthesis of nemorosone, a polyprenylated acyl­phloroglucinol isolated from Clusia rosea, was achieved by means of a bridgehead substitution process, involving initial iodination and subsequent lithium-iodine exchange followed by acylation. The difficulties in the bridgehead substitution are discussed, and a probable explanation proposed, based on molecular modelling.

Synthesis and Biological Evaluation of a New Family of Constrained Azabicyclic Homocholine Analogues

A family of constrained acylated homocholine analogues have been synthesized, based on the azabicyclic ring scaffold derived from a double-Mannich annulation of cyclic ketones. The short synthetic route allows generation of structural diversity including, variation in the carbocyclic ring size, bridgehead substitution, nitrogen substitution and the ester sidechain. Biological assays on selected analogues demonstrate these compounds are nicotinic acetylcholine receptor (nAChR) antagonists. Several analogues also bind to other neuronal transporter and receptor targets.

Effect of bridgehead substitution on the fluorescence quenching of 2,3-diazabicyclo[2.2.2]oct-2-enes by solvents and antioxidants

Azoalkanes of the 2,3-diazabicyclo[2.2.2]-oct-2-ene type have been introduced as probes for antioxidants in homogeneous solution as well as in liposomes and micelles. The bimolecular fluorescence quenching of the bridgehead dichloro-substituted 1,4-dichloro-2,3-diazabicyclo[2.2.2]-oct-2-ene (3) was compared with that of the parent compound 2,3-diazabicyclo[2.2.2]-oct-2-ene (1) and the bridgehead-dialkylated compound 4-methyl-1-isopropyl-2,3-diazabicyclo[2.2.2]-oct-2-ene (2). Compound 3 showed a more efficient fluorescence quenching in C-H containing solvents (e.g., in n-hexane: 30 ns for 3 versus 340 ns for 1 and 770 ns for 2), but a less efficient quenching in aqueous solution (e.g., in deaerated H(2)O: 485 ns for 3 versus 420 ns for 1 and 340 ns for 2), and also by molecular oxygen (k(q)/10(9) M(-1) s(-1) = 0.32 for versus 2.5 for 1 and 1.9 for 2). Towards low-molecular weight antioxidants, compound 3 showed a significantly higher reactivity (e.g., for reduced glutathione: k(q)/10(9) M(-1) s(-1) = 1.8 for 3 versus 0.82 for 1 and 0.39 for 2), at the expense of a lower differentiation between the investigated antioxidants (lower selectivity). The increased reactivity of 3 and lower, as well as qualitatively different, selectivity is attributed to a combination of factors, most importantly the slightly increased excitation energy of 3 and its lower excited-state nucleophilicity. The latter was independently corroborated, besides its longer fluorescence lifetime in aqueous solution, through the trends in quenching rate constants of the azoalkanes 1-3 towards electron-deficient versus electron-rich lactone antioxidants of the benzofuranone type. While common inorganic buffer constituents caused no fluorescence quenching, significant quenching was observed, as a curiosity, for hydrogencarbonate (k(q)/10(6) M(-1) s(-1) = 1.7 for 3 versus 2.4 for 1 and 0.45 for 2), with a fully manifested kinetic deuterium isotope effect (k(q)(H(2)O)/k(q)(D(2)O) = 12) for 3.

Bridgehead Lithiation-Substitution of Bridged Ketones, Lactones, Lactams, and Imides: Experimental Observations and Computational Insights

The viability of bridgehead lithiation-substitution of bridged carbonyl compounds has been tested in the laboratory, and the results were rationalized with the aid of a computational study. Lithiation-substitution was found to be possible for ketones, lactones, lactams, and imides having small bridges, including examples having [3.2.1], [3.2.2], [3.3.1], [4.2.1], and [4.3.1] skeletons. Smaller systems, where the sum of the bridging atoms (S) was 5, for example [2.2.1] or [3.1.1] ketones or [2.2.1] lactams, did not undergo controlled bridgehead substitution. Ketones or lactams having a [2.2.2] structure also did not give bridgehead substitution. B3LYP calculations accurately predict this behavior with negative DeltaE(rxn) values being calculated for the successful deprotonations and positive DeltaE(rxn) values being calculated for the unsuccessful ones. NBO calculations were also performed on the anionic deprotonated species, and these show that some structures are best represented as bridgehead enolates and some are best represented as alpha-keto carbanions.

Synthetic studies towards garsubellin A: synthesis of model systems and potential mimics by regioselective lithiation of bicyclo[3.3.1]nonane-2,4,9-trione derivatives from catechinic acid

Bridgehead lithiations have successfully been carried out on substrates derived from catechinic acid, which possess the core bicyclo[3.3.1]nonane-1,3,5-trione structure present in garsubellin A. Using an external quench method, various electrophiles have been incorporated at the C-5 bridgehead position in a one-step process that appears to be sensitive to the substitution pattern on the bicyclic system. Regioselective lithiation at the C-3 sp(2) centre was achieved by changing the base used from LDA to LTMP. Following the introduction of a prenyl substituent by bridgehead substitution, annulation of a THF ring, analogous to that in garsubellin A, was possible via an epoxidation-ring opening sequence. Oxidative modification of the catechol substituent of the catechinic acid core was possible to give systems with muconic acid, ortho-quinone or furan 2-carboxylic acid side chains.

Functionalized Nanodiamonds Part I. An Experimental Assessment of Diamantane and Computational Predictions for Higher Diamondoids

The structures, strain energies, and enthalpies of formation of diamantane 1, triamantane 2, isomeric tetramantanes 3-5, T(d)-pentamantane 6, and D(3d)-hexamantane 7, and the structures of their respective radicals, cations, as well as radical cations, were computed at the B3LYP/6-31G* level of theory. For the most symmetrical hydrocarbons, the relative strain (per carbon atom) decreases from the lower to the higher diamondoids. The relative stabilities of isomeric diamondoidyl radicals vary only within small limits, while the stabilities of the diamondoidyl cations increase with cage size and depend strongly on the geometric position of the charge. Positive charge located close to the geometrical center of the molecule is stabilized by 2-5 kcal mol(-1). In contrast, diamondoid radical cations preferentially form highly delocalized structures with elongated peripheral C-H bonds. The effective spin/charge delocalization lowers the ionization potentials of diamondoids significantly (down to 176.9 kcal mol(-1) for 7). The reactivity of 1 was extensively studied experimentally. Whereas reactions with carbon-centered radicals (Hal)(3)C(*) (Hal=halogen) lead to mixtures of all possible tertiary and secondary halodiamantanes, uncharged electrophiles (dimethyldioxirane, m-chloroperbenzoic acid, and CrO(2)Cl(2)) give much higher tertiary versus secondary selectivities. Medial bridgehead substitution dominates in the reactions with strong electrophiles (Br(2), 100 % HNO(3)), whereas with strong single-electron transfer (SET) acceptors (photoexcited 1,2,4,5-tetracyanobenzene) apical C(4)-H bridgehead substitution is preferred. For diamondoids that form well-defined radical cations (such as 1 and 4-7), exceptionally high selectivities are expected upon oxidation with outer-sphere SET reagents.

Sterically crowded bicyclo[1.1.0]butane radical cations.

The variability of carbon-carbon single bonds by steric and electronic effects is probed by DFT calculations of sterically crowded bicyclo[1.1.0]butanes and their radical cations. The interplay of sterics and electronics on the gradual weakening and breaking of bonds was studied by investigating bridgehead substitution in 1,3-di-tert-butylbicyclo[1.1.0]butane and 2,2',4,4'-tetramethyl-1,3-di-tert-butylbicyclo[1.1.0]butane and geminal substitution in 2,2'-di-tert-butylbicyclo[1.1.0]butane and 2,2',4,4'-tetra-tert-butylbicyclo[1.1.0]butane. Bridgehead substitution leads to a lengthening of the central bond, whereas bisubstitution on the geminal carbon leads to a shortening of this bond due to a Thorpe-Ingold effect. Although the character of the central bond can be modulated by substitution and electron transfer over a range of 0.35 A, the state forbidden ring planarization does not occur. Sterically crowded bicyclo[1.1.0]butane radical cations are therefore promising candidates for the investigation of extremely long carbon-carbon single bonds.