Synthesis of Carbazole Alkaloids by Ring‐Closing Metathesis and Ring Rearrangement–Aromatization

Aprocess for the assembly of carbazole alkaloids has been developed on the basis of ring‐closing metathesis (RCM) and ringrearrangement–aromatization (RRA) as the key steps. This method is based on allyl Grignard addition to isatin derivatives to provide smooth access to 2,2‐diallyl 3‐oxindole derivatives through a 1,2‐allyl shift. The diallyl derivatives were used as RCM precursors to afford a novel class of spirocyclopentene‐3‐oxindole derivatives, which underwent a novel RRA reaction to afford carbazole derivatives. The synthetic sequence to carbazoles was shortened by combining the RCM and RRA steps in an orthogonal tandem catalytic process. The utility of this methodology was further demonstrated by the straightforward synthesis of carbazole alkaloids, including amukonal derivative, girinimbilol, heptaphylline, and bis(2‐hydroxy‐3‐methylcarbazole).     

Enantioselective Synthesis of Macrocyclic Heterobiaryl Derivatives of Molecular Asymmetry by Molybdenum‐Catalyzed Asymmetric Ring‐Closing Metathesis

Winding vine‐shaped molecular asymmetry is induced by enantioselective ring‐closing metathesis with a chiral molybdenum catalyst. The reaction proceeds under mild conditions through an E‐selective ring‐closing metathesis leading to macrocyclic bisazoles with enantioselectivities of up to 96 % ee.     

Ring‐Closing Metathesis Reactions: Interpretation of Conversion–Time Data

Conversion–time data were recorded for various ring‐closing metathesis (RCM) reactions that lead to five‐ or six‐membered cyclic olefins by using different precatalysts of the Hoveyda type. Slowly activated precatalysts were found to produce more RCM product than rapidly activated complexes, but this comes at the price of slower product formation. A kinetic model for the analysis of the conversion–time data was derived, which is based on the conversion of the precatalyst (Pcat) into the active species (Acat), with the rate constant k_act, followed by two parallel reactions: 1) the catalytic reaction, which utilizes Acat to convert reactants into products, with the rate k_cat, and 2) the conversion of Acat into the inactive species (Dcat), with the rate k_dec. The calculations employ two experimental parameters: the concentration of the substrate (c(S)) at a given time and the rate of substrate conversion (?dc(S)/dt). This provides a direct measure of the concentration of Acat and enables the calculation of the pseudo‐first‐order rate constants k_act, k_cat, and k_dec and of k_S (for the RCM conversion of the respective substrate by Acat). Most of the RCM reactions studied with different precatalysts are characterized by fast k_cat rates and by the k_dec value being greater than the k_act value, which leads to quasistationarity for Acat. The active species formed during the activation step was shown to be the same, regardless of the nature of different Pcats. The decomposition of Acat occurs along two parallel pathways, a unimolecular (or pseudo‐first‐order) reaction and a bimolecular reaction involving two ruthenium complexes. Electron‐deficient precatalysts display higher rates of catalyst deactivation than their electron‐rich relatives. Slowly initiating Pcats act as a reservoir, by generating small stationary concentrations of Acat. Based on this, it can be understood why the use of different precatalysts results in different substrate conversions in olefin metathesis reactions.     

Temporary Silicon‐Tethered Ring‐Closing Metathesis: Recent Advances in Methodology Development and Natural Product Synthesis

Temporary silicon‐tethered ring‐closing metathesis represents an important cross‐coupling strategy for the formation of medium‐sized silacycles. These intermediates are valuable synthons in organic synthesis due to their propensity to undergo a facile refunctionalization through protodesilylation, oxidation, silane‐group transfer or transmetallation. A particularly attractive utility of this methodology is an application in the synthesis of biologically important natural products. The purpose of this review article is to highlight the recent progress in methodology development and its strategic application toward the target‐directed synthesis.     

Stereocontrolled Synthesis of Functionalized Azaheterocycles from Carbocycles through Oxidative Ring Opening/Reductive Ring Closing Protocols

Fluorine‐containing organic scaffolds are of significant interest in medicinal chemistry. The incorporation of fluorine into biomolecules can lead to remarkable changes in their physical, chemical, and biological properties. There are already many drugs on the market, which contain at least one fluorine atom. Saturated functionalized azaheterocycles as bioactive substances have gained increasing attention in pharmaceutical chemistry. Due to the high biorelevance of organofluorine molecules and the importance of N‐heterocyclic compounds, selective stereocontrolled procedures to the access of new fluorine‐containing saturated N‐heterocycles are considered to be a hot research topic. This account summarizes the synthesis of functionalized and fluorine‐containing saturated azaheterocycles starting from functionalized cycloalkenes and based on oxidative ring cleavage of diol intermediates followed by ring expansion with reductive amination.     

A New Synthesis of Benzofurans from Phenols via Claisen Rearrangement and Ring‐Closing Metathesis

Based on Claisen rearrangement, the double bond isomerization of O‐allyl function together with the formation of O‐vinyl function in one pot, and ring‐closing metathesis (RCM), various phenols were transformed into various benzofurans in good yields.     

A Formal Total Synthesis of Eleutherobin Using the Ring‐Closing Metathesis (RCM) Reaction of a Densely Functionalized Diene as the Key Step: Investigation of the Unusual Kinetically Controlled RCM Stereochemistry

Asymmetric oxyallylation reactions and ring‐closing metathesis have been used to synthesize compound 3 , a key advanced intermediate used in the total synthesis of eleutherobin reported by Danishefsky and co‐workers. The aldehyde 6 , which is readily prepared from commercially available R‐(?)‐carvone in six steps in 30 % overall yield on multigram quantities, was converted into the diene 5 utilizing two stereoselective titanium‐mediated Hafner–Duthaler oxyallylation reactions. The reactions gave the desired products ( 8 and 12 ) in high yields (73 and 83 %, respectively) as single diastereoisomers, with the allylic alcohol already protected as the p‐methoxyphenyl (PMP) ether, which previous work has demonstrated actually aids ring‐closing metathesis compared to other protective groups and the corresponding free alcohol. Cyclization under forcing conditions, using Grubbs' second‐generation catalyst 13 , gave the ten‐membered carbocycle (E)‐ 14 in 64 % yield. This result is in sharp contrast to similar, but less functionalized, dienes, which have all undergone cyclization to give the Z stereoisomers exclusively. A detailed investigation of this unusual cyclization stereochemistry by computational methods has shown that the E isomer of the ten‐membered carbocycle is indeed less thermodynamically stable than the corresponding Z isomer. In fact, the selectivity is believed to be due to the dense functionality around the ruthenacyclobutane intermediate that favors the trans‐ruthenacycle, which ultimately leads to the less stable E isomer of the ten‐membered carbocycle under kinetic control. During the final synthetic manipulations the double bond of enedione (E)‐ 16 isomerized to the more thermodynamically stable enedione (Z)‐ 4 , giving access to the advanced key‐intermediate 3 , which was spectroscopically and analytically identical to the data reported by Danishefsky and co‐workers, and thereby completing the formal synthesis of eleutherobin.     

Ring‐Closing Metathesis on an Allyl‐Terminated Carbosilane Dendrimer

Grubbs' catalyst was used to prepare a series of carbosilane dendrimers with silacyclopentene peripheral groups, suitable for further elaboration to functional dendrimers. The efficiency of the ring closing metathesis reaction was found to be strongly dependent on the reaction temperature and the amount of catalyst used, as shown by ¹H NMR monitoring.     

Ring‐Closing Olefin Metathesis for the Synthesis of Benzene Derivatives

Benzene derivatives were synthesized in excellent yield from 1,4,7‐trien‐3‐ols by tandem ruthenium‐catalyzed ring‐closing olefin metathesis (RCM)/dehydration. The method was extended to the tandem RCM/oxidation process to obtain phenol and aniline derivatives. This method displays many advantages over aromatic‐substitution‐based classical routes.     

Total Synthesis of (+)‐Cryptocaryalactone and of a Diastereoisomer of (+)‐Strictifolione via Ring‐Closing Metathesis (RCM) and Olefin Cross‐Metathesis (CM)

Ring‐closing metathesis (RCM) and olefin cross‐metathesis (CM) reactions were used as the key steps for the synthesis of (+)‐cryptocaryalactone ( 1 ) and the first synthesis of the diastereoisomer 3 of (+)‐strictifolione, starting from the commercially available L ‐malic acid (=(2S)‐2‐hydroxybutanedioic acid).     

Synthesis of 3‐Aryl‐2,5‐Dihydro‐1‐Benzoxepines from Phenol via Ring‐Closing Metathesis

In this paper, the synthesis of 3‐aryl‐2,5‐dihydro‐1‐benzoxepines is described. While the reaction was started from phenol and based on the sequential reactions such as Claisen rearrangement, O‐alkylation, Wittig reaction, and ring‐closing metathesis (RCM), a series of new 3‐aryl‐1‐benzoxepines were prepared in good overall yields.     

An [(NHC)(NHCEWG)RuCl2(CHPh)] Complex for the Efficient Formation of Sterically Hindered Olefins by Ring‐Closing Metathesis

NHC with EWGs for RCM : Ruthenium complexes with two N‐heterocyclic carbenes (NHCs), one of them substituted with electron‐withdrawing groups (EWGs), are highly efficient (pre)catalysts for the synthesis of tetrasubstituted olefins and trisubstituted olefins by ring‐closing metathesis reactions (RCM, see scheme).

     

Phosphate‐Tether‐Mediated Ring‐Closing Metathesis for the Preparation of Complex 1,3‐anti‐Diol‐Containing Subunits

An array of examples of diastereoselective, phosphate‐tether‐mediated ring‐closing metathesis reactions, which highlight the importance of product ring size and substrate stereochemical compatibility, as well as complexity, is reported. Studies focus primarily on the formation of bicyclo[n.3.1]phosphates, involving the coupling of C₂‐symmetric dienediol subunits with a variety of simple, as well as complex, alcohol partners.