Transannular Diels Research Articles

Distortion, Tether, and Entropy Effects on Transannular Diels–Alder Cycloaddition Reactions of 10–18-Membered Rings

Density functional theory calculations were performed on a set of 13 transannular Diels-Alder (TADA) reactions with 10-18-membered rings. The results were compared with those for bimolecular and intramolecular Diels-Alder reactions in order to investigate the controlling factors of the high TADA reactivities. The effects of tether length, heteroatoms, and alkynyl dienophiles on reactivity were analyzed. We found a correlation between tether length and reactivity, specifically with 12-membered macrocycles undergoing cycloaddition most readily. Furthermore, modifying 12-membered macrocycles by heteroatom substitution and utilizing alkynyl dienophiles enhances the reaction rates up to 10(5)-fold.

A model approach towards the polycyclic framework present in cembranoid natural products dissectolide A, plumarellide and mandapamate

A macrocyclic furanobutenolide was crafted from readily available furan building-blocks to set-up a transannular Diels–Alder reaction which delivered the carbocyclic core present in a class of cembranoid diterpene natural products.

Factors controlling the facility of transannular Diels-Alder reactions of macrocyclic bis-enones.

The reactivity of macrocyclic bis-enones in Diels-Alder reactions was examined using quantum chemical calculations. Stepwise pathways for these transannular cycloaddition reactions were shown to predominate. Steric interactions and torsional strain appeared to play a major role in controlling the overall barrier for polycycle formation.

Increasing the Efficiency of the Transannular Diels–Alder Strategy via Palladium(II)-Catalyzed Macrocyclizations

Palladium(II)-catalyzed macrocyclizations of bis(vinylboronate ester) compounds are demonstrated to provide a strategically efficient approach to transannular Diels-Alder reaction substrates. In several systems reported, the macrocycle is preorganized such that cycloaddition at room temperature occurs concomitantly with cyclization. Numerous advantages over palladium(0)-catalyzed cross-coupling approaches are demonstrated.

Role of conformational properties on the transannular Diels–Alder reactivity of macrocyclic trienes with varying linker lengths

The effect of the linker length (–CH2–) connecting the diene and the dienophile in macrocyclic trienes on their transannular Diels–Alder (TADA) reactivity has been investigated using density functional theory (DFT) calculations. The relationship between the conformational properties of these reactants and their reaction energy barriers was examined and a quantitative relationship has been obtained. The transition state energy barriers were found to increase with an increase in the linker length, which is in contrast to the expected trend. The conformational preferences of the triene reactants were studied using replica exchange molecular dynamics (REMD) simulations. These calculations reveal that longer linkers lead to a decreased probability of the occurrence of conformations with the diene and dienophile parts of the system vicinal to each other, and thus lower reactivity of systems with long linkers. Excellent correlations between the transition state energies and the cumulative probabilities corresponding to a short distance between the reactive sites, along with the ability of the diene to exist in the s-cisoid form, were observed.

Transannular Diels–Alder Reactivities of 14-Membered Macrocylic Trienes and Their Relationship with the Conformational Preferences of the Reactants: A Combined Quantum Chemical and Molecular Dynamics Study

Transannular Diels-Alder (TADA) reactions that occur between the diene and dienophile moieties located on a single macrocyclic triene molecule have been recognized as effective synthetic routes toward realizing complex tricyclic molecules in a single step. In this paper, we report a comprehensive study on the TADA reactions of 14-membered cyclic triene macrocycles to yield A.B.C[6.6.6] tricycles using quantum chemical methods and using classical molecular dynamics simulations. A benchmark study has been performed to examine the reliability of the commonly used ab initio methods and hybrid density functional levels of theory in comparison with results from CCSD(T) calculations to accurately model TADA reactions. The energy barriers obtained using the M06-2X functional were found to be in quantitative agreement with the CCSD(T) level of theory using a reasonably large basis set. Conformational properties of the reactants have been systematically studied using extensive molecular dynamics (MD) simulations. For this purpose, model systems were conceived, and force field parameters corresponding to the dihedral terms in the potential energy function were obtained. Linear relationship between the activation energies corresponding to the TADA reactions and the probability of finding the reactant in certain conformational states was obtained. A clustering method along with optimizations at the molecular mechanics and density functional M06-2X levels has been used to locate the most stable conformation of each of the trienes.

Synthetic studies on (+)-bucidarasin C: two diastereoselective transannular reactions producing cis-decaline derivatives that show reversal selectivity

This manuscript describes studies on the construction of the cis-decaline core of (+)-bucidarasin C. The transannular Diels–Alder (TADA) reaction of a macrocyclic lactone successfully afforded the desired cis-decaline derivative in a stereoselective manner. On the other hand, the stereoselective transannular cascade Michael (TACM) reaction of the parent macrocyclic lactone afforded the diastereomeric cis-decaline derivative as the major product.

Exploration of a proposed biomimetic synthetic route to plumarellide. Development of a facile transannular Diels–Alder reaction from a macrocyclic enedione leading to a new 5,6,7-tricyclic ring system

A concise synthesis of the macrocyclic vinylbutenolide 19 is described, based on a facile RCM reaction of the substrates 16/ 18. Treatment of 19 with TFA containing water led to the 5,6,7-tricyclic compound 27, in a single step, in >90% yield, rather than to the alternative ring system 23 found in plumarellide ( 1). A rationale for the formation of 27 is presented, involving initial acid-catalysed hydrolysis of the furanmethanol intermediate 20 to the furanoxonium ion 21, which is next hydrolysed to the enol ether cyclic hemiketal 22. The intermediate 22 undergoes rapid tautomerisation and isomerisation producing enedione 24, which then takes part in a transannular Diels–Alder cyclisation to 26. Dehydration of 26 finally produces the tricyclic compound 27.

ChemInform Abstract: Total Asymmetric Synthesis of the Aphidicolin Derivative (11R)-(-)-8-Epi-11-hydroxyaphidicolin Using Tandem Transannular Diels-Alder/Aldol Reactions.

Aphidicolin unnatural derivative (2) was synthesized using a new tandem transannular Diels−Alder/aldol methodology. The 8-epi-aphidicolane skeleton is constructed in a highly diastereoselective manner and converted into (11R)-(−)-8-epi-11-hydroxyaphidicolin (2). An efficient method for the difficult C16 funtionalization is presented.

Total Synthesis of (+)-Superstolide A

A convergent and highly stereocontrolled total synthesis of the cytotoxic macrolide (+)-superstolide A is described. Key features of this synthesis include the use of bimetallic linchpin 36b for uniting the C(1)-C(15) (43) and the C(20)-C(27) (38) fragments of the natural product, a late-stage Suzuki macrocyclization of 49, and a highly diastereoselective transannular Diels-Alder reaction of macrocyclic octaene 4. In contrast, the intramolecular Diels-Alder reaction of pentaenal 5 provided the desired cycloadduct with lower stereoselectivity (6:1:1).

Multiple chirality transfers in the enantioselective synthesis of 11- O-debenzoyltashironin. Chiroptical analysis of the key cascade

The mechanism of the cascade oxidative dearomatization–transannular Diels–Alder was investigated in the context of an asymmetric route to (−)-11- O-debenzoyltashironin. Although the oxidative dearomatization provides two acetal intermediates, the transannular Diels–Alder proceeds spontaneously from only one of the acetal isomers. Access to enantioenriched tetracyclic adduct was gained through the use of optically active allene.

ChemInform Abstract: Total Synthesis of (‐)‐Spinosyn A (Ib): Examination of Structural Features that Govern the Stereoselectivity of the Key Transannular Diels—Alder Reaction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Total Synthesis of (+)-Superstolide A

A convergent and highly stereocontrolled synthesis of +-superstolide A (1) has been accomplished. Key steps of this synthesis include the intramolecular Suzuki reaction of 26 and the highly diastereoselective transannular Diels-Alder cyclization of macrocyclic octaene 3.

Total Synthesis of (−)-Spinosyn A: Examination of Structural Features That Govern the Stereoselectivity of the Key Transannular Diels−Alder Reaction

A study of elements of stereochemical control in transannular Diels-Alder reactions leading to the decahydro-as-indacene core of (-)-spinosyn A is described. Initial studies focused on macrocyclic pentaene 9, which includes C(6)-Br and C(8)-OTBS substituents. Excellent selectivity (>95:5) was observed in the cycloaddition of 9 as a consequence of 1,3-allylic strain interactions involving the C(6) and C(8) substituents in the disfavored TS-2. The major cycloadduct 22 was used in a formal synthesis of (-)-spinosyn A. The TDA cyclizations of 12 (which lacks the C(8)-OTBS unit of 9), 13 (which lacks the C(6)-Br substituent of 12), and 14 (which lacks the C(6)-Br and C(21)-Et substituents of 12) were also studied. Macrocycles 12 and 13 served as precursors to (-)-spinosyn A and the (-)-spinosyn A aglycon (34), respectively. It is striking that substrates 12-14 give very similar distributions of transannular Diels-Alder cycloadducts, indicating that the C(6)-Br and C(21)-stereocenter do not play a significant role in the diastereoselectivity of the TDA cycloaddition of spinosyn A precursor 12. It is likely that some as yet unidentified conformational or structural features of macrocycles 12-14 contribute to the levels of diastereoselectivity achieved, since these TDA reactions are more selective for the C(7)-C(9) stereochemical relationship found in the natural product than are the IMDA reactions of trienes 4 and 7.

ChemInform Abstract: Asymmetric Catalysis of the Transannular Diels—Alder Reaction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Studies Toward the Total Synthesis of Nakiterpiosin: Construction of the CDE Ring System by a Transannular Diels—Alder Strategy.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Formal synthesis of tubelactomicins via a transannular Diels–Alder approach

A formal synthesis of the antimicrobial tricyclic macrolides, tubelactomicins A and E, featured by a transannular Diels–Alder (TADA) approach, has been explored. The key issue for the transannular cyclization was the synthesis of a 24-membered macrolactone equipped with all the requisite functionalities, which has been achieved using an intramolecular Hiyama cross-coupling strategy. The Hiyama coupling reaction spontaneously triggered off the TADA reaction. From the endo-TADA adduct, formal syntheses of tubelactomicins A and E were achieved. The 24-membered macrolactone formation was also achieved via an intramolecular ring-closing metathesis approach.

Studies toward the total synthesis of nakiterpiosin: construction of the CDE ring system by a transannular Diels–Alder strategy

The transannular Diels–Alder (TADA) reaction was applied to the synthesis of the CDE ring system of nakiterpiosin ( 1). Tetracyclic compound 25 may be a key intermediate in the total synthesis of 1.

A Diels–Alder Approach to (−)‐Ovalicin

A fascinating aspect of the Diels–Alder reaction is its endo selectivity. This endo preference is much less pronounced in intermolecular cases compared with the intramolecular and transannular Diels–Alder (IMDA and TADA) reactions. Nevertheless, high endo selectivity is observed in the Diels– Alder additions of (E)-1-O-substituted dienes catalyzed by Lewis acids that lead to cis-1,6-disubstituted cyclohexene systems of type I (Scheme 1). Compounds of type I could be

A Tether Controlled exo-Selective Trans-Annular Diels−Alder (TADA) Reaction

[reaction: see text] A fully substrate controlled stereoselective route to construct cis-hexahydronaphthalene 4 is described starting from nonracemic butenolide 6. The key step is an exo-selective transannular Diels-Alder reaction (TADA) of tetraene 5, whose intrinsic constraint allows selective formation of one stereodefined product. Compound 4 is a key intermediate in the synthesis of the novel antibiotic branimycin (1).