Bridgehead Olefins Research Articles

EBC‐219: A New Diterpene Skeleton, Crotinsulidane, from the Australian Rainforest Containing a Bridgehead Double Bond

AbstractEBC‐219 (4), isolated from Croton insularis (Baill), was established by spectroscopic and DFT methods as the first member of a new diterpene skeletal class, uniquely defined by the presence of a bicyclo[10.2.1] bridgehead olefin. The proposed biogenetic pathway to 4 from the co‐isolated natural products EBC‐131 (1), EBC‐180 (2) and EBC‐181 (3) is highly likely. EBC‐180 (2) and EBC‐181 (3) showed moderate to strong cytotoxic activity against various cancer cell lines.

Scalable enantioselective total synthesis of taxanes

Taxanes are a large family of terpenes comprising over 350 members, the most famous of which is Taxol (paclitaxel) — a billion-dollar anticancer drug. Here, we describe the first practical and scalable synthetic entry to these natural products via a concise preparation of (+)-taxa-4(5),11(12)-dien-2-one, which possesses a suitable functional handle to access more oxidised members of its family. This route enabled a gram-scale preparation of the ”parent” taxane, taxadiene, representing the largest quantity of this naturally occurring terpene ever isolated or prepared in pure form. The taxane family’s characteristic 6-8-6 tricyclic system containing a bridgehead alkene is forged via a vicinal difunctionalisation/Diels–Alder strategy. Asymmetry is introduced by means of an enantioselective conjugate addition that forms an all-carbon quaternary centre, from which all other stereocentres are fixed via substrate control. This study lays a critical foundation for a planned access to minimally oxidised taxane analogs and a scalable laboratory preparation of Taxol itself.

Microwave Assisted Synthesis of Bridgehead Alkenes

A new, concise method to synthesize triene precursors for the type 2 intramolecular Diels-Alder reaction has been developed. Microwave irradiation of the trienes provides a convenient method for the synthesis of bridgehead alkenes. Higher yields, shorter reaction times, and lower reaction temperatures provide a general and efficient route to this interesting class of molecules.

ChemInform Abstract: Intramolecular Enyne Metathesis Reaction. Route to Bridged Bicycles with Bridgehead Olefins.

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ChemInform Abstract: Influence of Strain on Chemical Reactivity. Relative Reactivity of Torsionally Strained Double Bonds in 1,3-Dipolar Cycloadditions.

The addition of picryl azide to a series of mono- and bicyclic olefins including trans-cycloalkenes and bridgehead alkenes is reported. Secondary reaction products were identified, and their mechanism of formation was explained by an analysis relating the transition state energies to the conformation of the reaction intermediates. Bridgehead alkenes showed reversed regiochemistry of cycloaddition when compared with model alkenes. It is proposed that the reversal of regiochemistry is caused by the out of plane bending of the bridgehead double bond

Bridgehead enolates and bridgehead alkenes in a welwistatin model series

Bridgehead metallation is possible in a ketone having the welwistatin skeleton, and this facilitates installation of the isothiocyanate function present in the natural product, and also enables synthesis of remarkable bridgehead alkenes.

Type 2 Intramolecular N-Acylazo Diels−Alder Reaction: Regio- and Stereoselective Synthesis of Bridgehead Bicyclic 1,2-Diazines

The type 2 intramolecular N-acylazo Diels-Alder reaction provides a regio- and stereoselective synthesis of bicyclic 1,2-diazine systems. A new method for the generation of N-acylazo dienophiles with tetra-n-butylammonium periodate is reported. X-ray crystallographic analysis allowed the quantification of structural distortions of the nonplanar bridgehead olefin and lactam functionalities in 1,2-diazine cycloadducts 11 and 15. Caprolactams and enantholactams were formed by stereoselective bridgehead alkene reduction, a process that transfers stereochemistry from the bridgehead lactam nitrogen to the bridgehead carbon. The sequence of transformations offers a convenient route for the diastereoselective synthesis of medium-ring nitrogen heterocycles and 1,4-diamines.

Reactions of endo-3-Diazotricyclo[3.2.1.02,4]oct-6-ene, a Potential Precursor for the Generation of a Neutral C8H8 Molecule with a Pyramidally Coordinated Carbon

endo-3-Diazotricyclo[3.2.1.0(2,4)]oct-6-ene (endo-6) has already been prepared in solution. According to B3LYP/6-311+G(d,p) computations, the corresponding carbene endo-7 easily produces the highly strained neutral C8H8 compound 4 comprising a pyramidally tetracoordinated carbon which then rearranges to bridgehead alkene 15 through a cascade of rearrangements. Nonplanar diazocyclopropane structures are predicted for endo- and exo-6. Furthermore, their ring-opened isomers 27 are the first representatives of a new class of non-Kekulé compounds, the diazoallyls.

Metalation of 9‐Oxabicyclo[3.3.1]nonadiene – the Deprotonation Path to Bridgehead Olefins

AbstractA new route to bridgehead olefins based on a deprotonation reaction has been established. The deprotonation of 9‐oxabicyclo[3.3.1]nonadiene (1) with tBuLi/TMEDA occurs selectively in the allylic position. Whilst 1 has four allyl positions, only one bridgehead proton was removed, as demonstrated by quenching with Me3SnCl, Me3SiOTf, and Me3PbCl. With a threefold excess of deprotonating agent and subsequent treatment with Me3SnCl, three stannylated derivatives – 3, 4a, and 4b – were obtained. Compound 3 is the starting diene 1 substituted at the bridgehead position 1 in the skeleton, and when smaller quantities of deprotonating agent were used it was the only stannylated derivative of 1 formed. Compounds 4a and 4b had each undergone a shift of one double bond to give bridgehead olefins exo‐ and endo‐stannylated at position 3 in the skeleton. The common intermediate precursor of compounds 3, 4a, and 4b was a bridgehead allyl anion, which can also be generated from 3 and could be observed directly by 6Li and 13C NMR spectroscopy. After quenching of the anion with Me3SiOTf, and Me3PbCl, two silylated and plumbylated derivatives of 1 were obtained in each case: the bridgehead‐substituted compounds and the 3‐exo‐substituted bridgehead olefins. The stannylated bridgehead olefins 4a and 4b rearranged slowly to give 3 in what is formally a 1,3‐stannatropic shift reaction. The kinetics of the reactions are zero‐order in 4a and 4b, respectively, pointing to intermediate light‐promoted homolytic cleavage of the Sn–C bond and the formation of a tight radical pair.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Palladium-mediated fragmentation of meta photocycloadducts using carbon based electrophiles. Part 1

Substituted benzene derived meta photocycloadducts have been shown to undergo a fragmentation/arylation reaction under Heck reaction conditions to give bridged bicyclo[3.2.1] compounds in a highly atom-efficient manner. When an anisole derived meta photocycloadduct is used, a bridgehead ketone is generated. However, if an alkylbenzene derived meta photocycloadduct is used, a bridgehead alkene is formed. This strategy has been used to create novel enol ether and transient allyl silane compounds.

A 1-Norbornene Adduct of a Transition Metal and an Electrochemical Study of the Bridgehead Olefin Complex

Treatment of a slurry of (PCy3)2NiCl2 in pentane with 1-norbornyllithium did not lead to the expected bis(1-norbornyl) nickel complex but instead led to formation of a 1-norbornene adduct, which has been structurally characterized. The X-ray data and the electrochemistry of the 1-norbornene complex suggest a metallacyclopropane extreme of olefin binding, stemming from the highly reactive nature of the bridgehead double bond.

Molecular Modeling of Anti-Bredt Compounds

The molecular structure and thermochemical stability of 40 bicyclic alkenes and imines containing between five and eight heavy atoms has been investigated computationally by high-level G3/B3LYP method. The same method was also used to study their building blocks: monocyclic alkenes and imines. The relative stability of isomers, standard enthalpies of formation and strain energies are discussed and compared. Our results suggest that molecular mechanics provides an unsatisfactory description of strain energies in bridgehead alkenes. Some bridgehead alkene and imine species represent structures which are not local minima on the potential energy surface and are hence unlikely to be isolated. Furthermore, some bicyclic alkenes and imines have open-shell 1,2-diradical character.

Synthetic Studies Related to CP‐225,917

AbstractFor Abstract see ChemInform Abstract in Full Text.

The room-temperature stabilization of bicyclo[2.2.2]oct-1-ene and bicyclo[3.2.1]oct-1-ene.

Retardation through incarceration: The highly strained anti-Bredt bridgehead olefin bicyclo[2.2.2]oct-1-ene (1) is remarkably stable at 60 °C, if generated photochemically inside the hemicarcerand 2 (see picture). The surrounding host not only prevents the dimerization of 1, but also retards strongly its intramolecular retro-Diels–Alder reaction by several orders of magnitude.

Synthetic studies related to CP-225,917

Synthetic studies related to CP-225,917 are described, including the preparation of the fully oxygenated tetracyclic central core 3.Key words: CP-225,917, siloxy-Cope rearrangement, Cope rearrangement, strain-assisted rearrangement, furan, ruthenium dioxide, bridgehead olefin.

An enantioselective synthesis of FR182877 provides a chemical rationalization of its structure and affords multigram quantities of its direct precursor.

The evolution of a strategy culminating in an efficient, enantioselective synthesis of the potent microtubule-stabilizing agent FR182877 is described. Guided by a proposed biogenesis of this complex natural product, a solution emerged that involved the first reported example of a double transannular Diels-Alder reaction to fashion the key elements of its hexacyclic structure. This pivotal transformation creates a complex pentacycle from a 19-membered macrocyclic pentaene, forming seven new stereogenic centers in a fully diastereocontrolled fashion. The efficiency of the approach ultimately enabled the preparation of multigram quantities of the direct precursor of FR182877 for conversion to the relatively unstable natural product when required. The reactivity of the strained, bridgehead olefin of this secondary metabolite with biologically relevant nucleophiles is also described.

Synthesis of the racemic tetracyclic core of CP-225,917—a model compound lacking the sidearms of the natural product

Compound 3 , representing the tetracyclic core structure of CP-225,917, was prepared from bridgehead olefin 9 , which was first converted into ketone 13 . Peterson olefination then gave 15 , and this was elaborated into the anhydride 19 , from which crystalline 3 was reached by a sequence of deprotection and oxidation steps.

The Type 2 Intramolecular Diels–Alder Reaction: Synthesis and Chemistry of Bridgehead Alkenes

Anti-Bredt alkenes, bicyclic molecules that contain a bridgehead double bond, were for many years regarded as chemical curiosities. The type 2 intramolecular Diels–Alder (IMDA) reaction provides a one-step entry into this fascinating class of molecules. The reaction has made available numerous anti-Bredt alkenes for structural and chemical studies. X-ray crystallography has revealed the magnitude of the deformations associated with the bridgehead double bond, and rate studies of reactions of bridgehead alkenes have allowed quantification of the kinetic consequences of the torsional distortions. More recently, the type 2 intramolecular Diels–Alder reaction and the resulting anti-Bredt alkenes have found application in organic synthesis. The constraints resulting from the connectivity in the Diels–Alder precursor creates a strong regio- and stereochemical bias in the cycloaddition step. The end result of this bias is the stereoselective synthesis of highly substituted six-membered rings. The reaction also achieves a facile synthesis of seven- and eight-membered rings in a single step from acyclic precursors. The utility of this reaction has been verified in recent applications of the type 2 IMDA reaction as a key step in the total synthesis of complex natural products.

The Type 2 Intramolecular Diels-Alder Reaction: Synthesis and Chemistry of Bridgehead Alkenes

Anti-Bredt alkenes, bicyclic molecules that contain a bridgehead double bond, were for many years regarded as chemical curiosities. The type 2 intramolecular Diels-Alder (IMDA) reaction provides a one-step entry into this fascinating class of molecules. The reaction has made available numerous anti-Bredt alkenes for structural and chemical studies. X-ray crystallography has revealed the magnitude of the deformations associated with the bridgehead double bond, and rate studies of reactions of bridgehead alkenes have allowed quantification of the kinetic consequences of the torsional distortions. More recently, the type 2 intramolecular Diels-Alder reaction and the resulting anti-Bredt alkenes have found application in organic synthesis. The constraints resulting from the connectivity in the Diels-Alder precursor creates a strong regio- and stereochemical bias in the cycloaddition step. The end result of this bias is the stereoselective synthesis of highly substituted six-membered rings. The reaction also achieves a facile synthesis of seven- and eight-membered rings in a single step from acyclic precursors. The utility of this reaction has been verified in recent applications of the type 2 IMDA reaction as a key step in the total synthesis of complex natural products.

Base-Promoted Reaction of a Cage Diketone. Novel Rearrangement to a Tricyclic Bridgehead Olefin

Caged diketone 1underwent the base-promoted reaction to produce bicyclo[2.2.1]heptenyl diacid 4and tricyclic ketone 5as major products. Tricyclic ketone 5possesses a bridgehead double bond embedded in a tricyclo[5.2.1.03,8]dec-2-ene ring skeleton. The structures of 4and 5were unambiguously established by X-ray crystal analyses.