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.     

Experimental and Computational Studies of Anti‐Bredt Amidinium Salts

Experimental and computational investigations of anti‐Bredt amidinium salts are presented. Calculations show that the pyramidalization of an amino group can significantly destabilize the formal carbocation center of amidiniums, due to the decreased π donation. In some cases, the unfavorable ‐I effect of nitrogen surpasses its beneficial +M effect, and amidiniums become less stable than iminiums. It is shown that although 1‐aza‐3‐azonia[3.3.1]bicyclo‐non‐2‐enes can be isolated, they feature a nonclassical reactivity, which is more typical for iminium than amidinium salts, such as pronounced electrophilicity and azomethineylide instead of carbene formation.     

A theoretical study for the regioselective Diels–Alder reaction of 5,6‐fulleroid with strained anti‐Bredt olefins

Regioselectivity of Diels–Alder reaction of the anti‐Bredt olefin of fulleroid, the 5,6‐methylene‐bridged fullerene derivative, is theoretically clarified by DFT calculations. In transition state calculations, the addition of a noncyclic diene 2,3‐dimethyl‐1,3‐butadiene (DMBD) at the anti‐Bredt olefin has considerably lower activation energy than those at the other sixteen olefins, while the reaction of a rigid cyclic diene cyclohexadiene (CHD) has similar activation energy at both anti‐Bredt and another nontwisted olefin. The changes in strain and interaction of the reactants are estimated along its reaction coordinate by activation strain model. Noncyclic diene shows asynchronous C? C bond formation with a significant gain of interaction energy, while the rigid cyclic diene shows a large growth of strain energy canceling out the interaction energy between diene and fulleroid.     

Do Anti‐Bredt Natural Products Exist? Olefin Strain Energy as a Predictor of Isolability

Bredt’s rule holds a special place in the realm of physical organic chemistry, but its application to natural products chemistry—the field in which the rule was originally formulated—is not well defined. Herein, the use of olefin strain (OS) energy as a readily calculated predictor of the stability of natural products containing a bridgehead alkene is introduced. Schleyer first used OS energies to classify parent bridgehead alkenes into “isolable”, “observable”, and “unstable” classes. OS calculations on natural products, using contemporary forcefield methods, unequivocally predict all structurally verified bridgehead alkene natural products to be “isolable”. Thus, when one assigns the structure of a putative bridgehead alkene natural product, an OS in the “observable” or “unstable” ranges is a red flag for error.     

Do Anti‐Bredt Natural Products Exist? Olefin Strain Energy as a Predictor of Isolability

Bredt’s rule holds a special place in the realm of physical organic chemistry, but its application to natural products chemistry—the field in which the rule was originally formulated—is not well defined. Herein, the use of olefin strain (OS) energy as a readily calculated predictor of the stability of natural products containing a bridgehead alkene is introduced. Schleyer first used OS energies to classify parent bridgehead alkenes into “isolable”, “observable”, and “unstable” classes. OS calculations on natural products, using contemporary forcefield methods, unequivocally predict all structurally verified bridgehead alkene natural products to be “isolable”. Thus, when one assigns the structure of a putative bridgehead alkene natural product, an OS in the “observable” or “unstable” ranges is a red flag for error.     

Searching the Chemical Space of Bicyclic Dienes for Molecular Solar Thermal Energy Storage Candidates

Photoswitches are molecular systems that are chemically transformed subsequent to interaction with light and they find potential application in many new technologies. The design and discovery of photoswitch candidates require intricate molecular engineering of a range of properties to optimize a candidate to a specific applications, a task which can be tackled efficiently using quantum chemical screening procedures. In this paper, we perform a large scale screening of approximately half a million bicyclic diene photoswitches in the context of molecular solar thermal energy storage using ab initio quantum chemical methods. We further device an efficient strategy for scoring the systems based on their predicted solar energy conversion efficiency and elucidate potential pitfalls of this approach. Our search through the chemical space of bicyclic dienes reveals systems with unprecedented solar energy conversion efficiencies and storage densities that show promising design guidelines for next generation molecular solar thermal energy storage systems.     

Chiroptical Properties – Structure Relationship in Bicyclic Isoxazolidin‐5‐one Derivatives

The relationship between chiroptical properties of substituted bicyclic isoxazolidin‐5‐one derivatives and their molecular structures was investigated. The chromophoric system in isoxazolidinones was found to be nonplanar with a shallow pyramidal configuration at the N‐atom. The deviation from planarity can be attributed to the strain imposed by the bicyclic skeleton. Due to the nonplanarity, the isoxazolidinone system becomes inherently dissymmetric, which is supported by the high magnitude of the CD band occurring around 210 nm. In addition, the helicity of lactone moiety in investigated bicyclic isoxazolidinones is controlled by the absolute configuration at C(6). On this basis, a helicity rule correlating a positive (negative) helicity expressed by the OC(8) O(9) N(1) torsional angle with a positive (negative) sign of the CD band around 210 nm was formulated.     

Nitrogen inversion in cyclic amines and the bicyclic effect

The hitherto unsolved problem of the origin of the unusually high nitrogen inversion-rotation (NIR) barriers in 7-azabicyclo[2.2.1]heptanes (the bicyclic effect) was examined using the natural bond orbital (NBO) approach. Reinvestigating the NIR barrier for tropane by DNMR, we found that NIR barriers increase smoothly on going from nitrogen-bridged bicyclic systems of a larger ring size to the smaller ring homologous systems. The experimental NIR barriers are reproduced with good accuracy using the MP2/6-31G level of theory. The NBO analysis for these and other azabicycles led to the conclusion that the height of these barriers is mostly determined by the energy of the sigma-orbitals of the C(alpha)(-)C(beta) bonds as well as the nitrogen lone pair. Thus, the bicyclic effect is actually an extreme case of a common C(alpha-)N-C(alpha) tripyramid geometry-NIR barrier dependence for N-bridged bicyclic amines. By establishing the rate-determining role of the C(alpha-)N-C(alpha) tripyramid fragment for NIR, we have derived the first sufficiently accurate quantitative correlations amine geometry-NIR barrier for monocyclic as well as bicyclic N-H and N-Me amines (i.e., for an amine set which also includes the bicyclic effect systems).     

Ring-expanded bicyclic β-lactams: a structure-chiroptical properties relationship investigation by experiment and calculations

In the present work, the validity of the helicity rule relating the absolute configuration of the bridgehead carbon atom in bicyclic β-lactams to the sign of the 220 nm band observed in their electronic circular dichroism (ECD) spectra is examined for ring-expanded cephalosporin analogues. To this end, a series of model compounds with a seven-membered ring condensed with the β-lactam unit was synthesized. A key step of their synthesis was either the ring-closing metathesis (RCM) or the free radical cyclization leading to the seven-membered ring with an S, O, or C atom at the 6 position in the bicyclic skeleton. To investigate the scope and limitations of the simple, empirically established helicity rule, a combination of ECD spectroscopy, variable-temperature ECD measurements, X-ray analysis, and time-dependent density functional theory (TD-DFT) calculations was used. A comparison of the experimental ECD spectra with the spectra simulated by TD-DFT calculations gives a reasonable interpretation of the Cotton effects observed in the 240-215 nm spectral range. The results suggest that the helicity rule does not apply to the investigated compounds because of the planarity of their amide chromophore. Thus, these compounds do not constitute an exception to the rule that was established for bi- and polycyclic β-lactams with the nonplanar amide chromophore only.     

Mass spectra of the substituted quinuclidines

The mass spectra of the quinuclidine-2 (and -3)-ones and other functional derivatives of quinuclidine as well as 2-azaquinuclidine and benzoquinuclidine have been investigated. The fragmentation through the open form of the molecular ion and the applicability of Bredt's rule to amine fragmentation of the bridgehead nitrogen bicyclic systems are discussed.     

Struktur/wirkung-Beziehungen bei Geruchsstoffen mit dem Bicyclo[2.2.2.]octan-Gerüst

Structure-Activity Relationships of Odorants with a Bicyclo[2.2.2]octane System The synthesis of the olfactory interesting homonojigikualcohol 2 and of its epimer 10 leads to the keto alcohols 6a, b and 7a, b as intermediates. The latter have OH and C?O groups (an AH/B system) fixed at the rigid bicyclic nucleus at different distances (2.8 and 4.7 Å) and confirm Ohloff's rule for odoriferous properties which is based on this distance.     

Circular dichroism and conformational dynamics of cephams and their carba and oxa analogues

The biological activity of bicyclic beta-lactam antibiotics depends strongly on the absolute configuration of the bridgehead carbon atom. Frelek and co-workers proposed an empirical helicity rule relating the configuration of the bridgehead carbon atom to the sign of the 220 nm band in the electronic circular dichroism (CD) spectrum of beta-lactams. Here we use synthetic organic chemistry, CD spectroscopy, and time-dependent density functional theory (TDDFT) to investigate the validity of this structure-property relationship for eight model compounds. For conformationally flexible beta-lactams, substantial thermal effects are found which must be included in calculations. To this end, we combine TDDFT calculations of CD with full quantum-mechanical Born-Oppenheimer molecular dynamics (MD) simulations for the first time. The CD spectra are sampled with ground-state density functional trajectories of up to 60 ps. The MD simulations show a surprisingly high sensitivity of the CD to the molecular conformation. On the other hand, the relation between CD and thermally averaged structural parameters is much less complex. While the helicity rule does not seem to hold for individual conformers, it is confirmed by the calculations for seven out of eight systems studied if thermally averaged CD spectra and structures are considered. Since thermal effects on CD can be larger than typical inherent inaccuracies of TDDFT, our results emphasize the need for a systematic treatment of conformational dynamics in CD calculations even for moderately flexible systems. Temperature-dependent CD measurements are very useful for this purpose. Our results also suggest that CD spectroscopy may be used as a sensitive probe of conformational dynamics if combined with electronic structure calculations.     

Ammonium based anion receptors

Selective anion recognition has been a tremendous challenge to chemists over the decades. However, with the advent of the concepts inherent in ‘supramolecular chemistry,’ the field now flourishes. Of the major types of receptors, polyamines have been studied widely as anion hosts by a number of researchers. Both electrostatic interactions and hydrogen bonds between protonated amines and the anion guests govern the binding in these systems. Exceptions to this rule are found in the quaternary ammonium systems, which utilize primarily electrostatic interactions and topological complementarity for binding purposes. This review focuses only on amine-based hosts, and is divided into acyclic and macrocyclic categories, the latter of which are based on cyclic dimension. The resulting four categories are: acyclic, monocyclic, bicyclic, and polycyclic. Within the major categories, binding is discussed according to the nature of the anion target, i.e. ‘simple’ inorganic anions, organic anions, and anionic metal complexes.     

Convenient Approach to 10- and 11-Membered Azalactams

A convenient method for the synthesis of 10- and 11-membered azalactams via reductive cleavage of bicyclic systems featuring an amidine fragment was studied. It was found that the ring-expansion reaction of bicyclic dihydropyrimidones depends on the ring size of saturated fragment, substituents in the pyrimidone core and reaction conditions. A new efficient method for the synthesis of medium ring azalactams by reductive cleavage of quaternary salts of annulated dihydropyrimidones was proposed as well. The obtained medium ring azalactams with a secondary amine function were used in the synthesis of bicyclic heteroaromatic systems.     

Heterocyclic steroids: Synthetic routes and biological characteristics of steroidal fused bicyclic pyrimidines

Natural steroids are characterized as a vital class of compounds, a type of secondary metabolites and components of cell membranes that widely accessible in plants or animals displayed significant pharmacological and varied biological properties. The present study aims to highlight the conveyed researches of synthetic routes adopted to obtain the various structures of steroidal fused bicyclic pyrimidines with substantial biological and pharmaceutical importance. The topic was discussed in light of the synthesis of fused [6 + 5] bicyclic systems, fused [6 + 6] bicyclic systems, binary heterocycles, and biological applications. In detail, the various synthetic strategies for the construction of steroids fused to bicyclic pyrazolopyrimidines, thiazolopyrimidines, triazolopyrimidines, pyridopyrimidines, pyranopyrimidines, and binary pyrimidines were discussed. Heterocyclic steroids of this class of compounds demonstrated potent anticancer, anti-proliferative, anti-neuro-inflammatory, anti-inflammatory, and anti-ulcer activities. It was perceived that the synthetic steroids of such bicyclic pyrimidine scaffolds are fused into the steroid basic skeleton is essential for the potent bioactivities.     

Molybdenum-mediated cleavage reactions of isoxazoline rings fused in bicyclic frameworks

The molybdenum-mediated cleavage reactions of isoxazoline rings fused in bicyclic frameworks were investigated. A tandem N-O bond cleavage-retro aldol reaction of an isoxazoline ring fused in a bicyclic framework led to the cleavage of the bicyclic framework. These reactions provide a novel stereoselective synthesis of substituted cyclopentene rings, cyclopentane rings, and attached-ring systems. [reaction: see text]     

Synthesis of cis-Fused Bicyclic Systems by Radical Cyclization Approach: Formal Synthesis of Ethisolide and iso-Avenaciolide

Formal synthesis of ethisolide and iso-avenaciolide was achieved using furanoid glycal-vinyl radical intermediates. The vinyl radical cyclization by 5-exo-dig mode gave the cis-fused bicyclic systems with an efficient introduction of the exo-methylene group, besides helping in the inversion of the adjacent stereocentre. Further, the study describes the synthesis of cis-fused bicyclic systems from L-arabinose and D-xylose for the creation of diverse natural and synthetic products of this class.     

Properties of stable organic bond-stretched non-Lewis molecules

The conditions required for the existence of a stable bond-stretched singlet isomer of hetero derivatives of bicyclo[2.1.0]pentane (which is a cyclopentane-1,3-diyl derivative) are discussed. Such species are non-Lewis systems with a ruptured C-C bond (formally diradicals), in which two electrons occupy the nonbonding orbital. A high-level calculation shows that in contrast with the carbon substituted compounds, in which the open form is a transition state between two classical-bonded closed bicyclic forms, in the heterosubstituted molecules, the open form is calculated to be a stable minimum. The ionization potentials of the open forms are considerably lower than those of their bicyclic isomers and also of regular organic radicals/diradicals. Nitrogen atoms are found to be more effective than oxygen or sulfur in stabilizing the open isomer. In this case, the open isomer is calculated to be a little more stable than the bicyclic compound, and a barrier of approximately 40 kcal/mol is computed for the ring closing reaction. Thus, the open isomer is both thermodynamically and kinetically stable. This result rationalizes some experimental observations that indicated the existence of non-Lewis singlet species.     

Domino ring-opening metathesis-ring-closing metathesis of bicyclo[2.2.2]octene derivatives: scope and limitations

Domino metathesis involving ring-opening metathesis-ring-closing metathesis (ROM-RCM) of a bicyclo[2.2.2]octene derivative having an appropriate alkene chain, expected to produce a 7/6 fused bicyclic system, provided a decalin system in contrast to ROM-RCM of the corresponding bicyclo[2.2.1]heptene analogues, which as expected produced the 7/5 fused bicycles. The expected 6/7 bicyclic system could, however, be made through RCM of the elusive ROM product prepared from the same bicyclo[2.2.2]octene analogue by a nonmetathetic route. A rationale to explain the difference in reactivity pattern between these two systems toward ROM-RCM has been forwarded.     

Transformations of bicyclic systems containing an isothiazole ring

Isothiazolium salts, which are readily hydrolyzed to heterocyclic o-formyl disulfides, were obtained by alkylating bicyclic systems containing an isothiazole ring. The initial isothiazole-containing systems are stable in water and react with nucleophiles such as the hydroxyl ion with opening of the isothiazole ring and formation of o-cyanodisulfides.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 223–226, February, 1985.