(−)‐Sparteine‐Mediated Directed ortho‐Metalation of N‐Cumyl‐N‐ethylferrocenecarboxamide. Versatile Routes to Functionalized Planar Chiral Ferrocenecarboxamides,Amines, Esters and Phosphines

N‐Cumyl‐N‐ethylferrocenecarboxamide 5 provides planar chiral carboxamides 6 in high yield and % ee via (−)‐sparteine‐mediated directed ortho‐metalation. Mild decumylation affords secondary amides 7 , which serve as intermediates for a convenient and general route to the venerable Ugi planar chiral ferrocenylamines 13 and as versatile precursors for the preparation of novel chiral ferrocenes 15 and 20 . The chiral TMS‐ferrocenyl derivative 7c is used to prepare the enantiomeric (S)‐ 7f , circumventing the lack of availability of (+)‐sparteine.     

Bismuth Triflate‐Catalyzed Addition of Allylsilanes to N‐Alkoxycarbonylamino Sulfones: Convenient Access to 3‐Cbz‐Protected Cyclohexenylamines

Bismuth triflate was found to be an efficient catalyst in the Sakurai reaction of allyltrimethylsilanes with N‐alkoxycarbonylamino sulfones. The reaction proceeded smoothly with a low catalyst loading of Bi(OTf)₃⋅4 H₂O (2–5 mol%) to afford the corresponding protected homoallylic amines in very good yields (up to 96%). A sequential allylation reaction followed by ring‐closing metathesis delivers 6–8 membered 3‐Cbz‐protected cycloalkenylamines.     

Progress towards the Stereoselective Synthesis of 3,6‐Disubstituted 1,2‐Diamino‐4‐cyclohexenes by Ring Closing Metathesis Reaction

The ring closing metathesis of 4(R),5(R)‐bis[1(S)‐phenylethylamino]‐3,6‐diethenyl‐1,7‐octadiene required the preliminary formation of the cyclic formaldehyde aminal, then the use of the Grubbs' ruthenium benzylidene complex (10 mol %) in refluxing toluene in the presence of 2 equivalents of trifluoroacetic acid. The cyclic aminal was cleaved in situ after the cyclisation step, so that the final product was the 1,2‐diamino‐3,6‐diethenylcyclohex‐4‐ene derivative. The predominant C₁‐symmetric diastereomer was isolated with 48% yield.     

Asymmetric Synthesis of β‐Substituted α‐Methylenebutyro‐ lactones via TRIP‐Catalyzed Allylation: Mechanistic Studies and Application to the Synthesis of (S)‐(−)‐Hydroxymatairesinol

Asymmetric allylation of (hetero)aromatic aldehydes by a zinc(II)‐allylbutyrolactone species catalyzed by a chiral BINOL‐type phosphoric acid gave β‐substituted α‐methylenebutyrolactones in 68 to >99% ee and 52–91% isolated yield. DFT studies on the intermediate Zn²⁺‐complex – crucial for chiral induction – suggest a six‐membered ring intermediate, which allows the phosphoric acid moiety to activate the aldehyde. The methodology was applied to the synthesis of the antitumour natural product (S)‐(−)‐hydroxymatairesinol.

     

Iridium‐Catalyzed Asymmetric Allylic Etherification and Ring‐Closing Metathesis Reaction for Enantioselective Synthesis of Chromene and 2,5‐Dihydrobenzo[b]oxepine Derivatives

Iridium‐catalyzed asymmetric etherifications of allylic carbonates with 2‐vinylphenols and 2‐allylphenols were realized. With a catalyst generated from 2 mol% of [Ir(cod)Cl]₂ (cod=cycloocta‐1,5‐diene) and 4 mol% of the phosphoramidite ligand L2 , the etherification products were obtained in excellent ees and then subjected to the ring‐closing metathesis reaction providing an efficient synthesis of enantioenriched 2H‐chromene and 2,5‐dihydrobenzo[b]oxepine derivatives.     

Formation of Arenes via Diallylarenes: Strategic Utilization of Suzuki–Miyaura Cross‐Coupling,Claisen Rearrangement and Ring‐Closing Metathesis

Two new synthetic strategies for benzoannulation are reported. The first strategy is based on the Suzuki–Miyaura cross‐coupling reaction. To this end, various ortho‐diallylbenzene derivatives were prepared from the corrresponding diiodo derivatives by an allylation strategy using an allylboronate as coupling partner. These diallyl derivatives were subjected to a ring‐closing metathesis (RCM) and one‐pot dichlorodicyanoquinone (DDQ) oxidation sequence to deliver 2‐substituted naphthalenes. In the second strategy, a double Claisen rearrangement and RCM protocol have been used as key steps to give highly functionalized benzoannulated quinone derivatives.     

Synthesis and characterization of 4,5‐bis(4‐fluorobenzoyl)‐1‐methylcyclohexene and its polyethers

A new difluoride 4,5‐bis(4‐fluorobenzoyl)‐1‐methylcyclohexene (DFKK) has been prepared with fumaryl chloride, fluorobenzene, and 2‐methyl‐1,3‐butadiene as starting materials through two steps of reactions. This DFKK monomer undergoes reaction with 2,2‐(p‐hydroxyphenyl)‐iso‐propane (BPA) in the presence of excess anhydrous potassium carbonate in sulfolane to give a high molecular weight reactive poly(ether ketone ketone) (PEKK) that is very soluble in solvents such as chloroform and N,N‐dimethylformamide at room temperature, has glass transition temperature of 182°C, and is easily cast into flexible and bale ivory film with tensile strength of 64 MPa. The 5% weight loss temperature is 407°C. Ring‐closing reaction of PEKK with hydrazine gives cyclized PEKK (CPEKK) with improved thermal stability and reduced solubility. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 84: 1866–1871, 2002; DOI 10.1002/app.10454     

Unexpected Results of a Turnover Number (TON) Study Utilising Ruthenium‐Based Olefin Metathesis Catalysts

A turnover number (TON) study of ruthenium‐based metathesis catalysts has been conducted for ring‐closing metathesis (RCM) in dilute solution. Unexpectedly the results indicate that 1^st generation metathesis catalysts can give higher TON in RCM of simple unsubstituted terminal olefins than their second generation counterparts. In particular, the 1^st generation Hoveyda–Grubbs catalyst showed unexpectedly high activity, particularly when compared to the 2^nd generation catalysts.     

New Indenylidene‐Schiff Base‐Ruthenium Complexes for Cross‐Metathesis and Ring‐Closing Metathesis

We here report on the stability and catalytic activity of new indenylidene‐Schiff base‐ruthenium complexes 3a – f through representative cross‐metathesis (CM) and ring‐closing metathesis (RCM) reactions. Excellent activity of the new complexes was found for the two selected RCM reactions; prominent conversion was obtained compared to the commercial Hoveyda–Grubbs catalyst 2 . Moreover, excellent results were obtained for a standard CM reaction. Higher conversions were achieved with one of the indenylidene catalysts compared with Hoveyda–Grubbs catalyst. Unexpectedly, an isomerization reaction was observed during the CM reaction of allylbenzene. To the best of our knowledge, isomerization reactions in this model CM reaction in closed systems have never been described using first generation catalysts, including the Hoveyda–Grubbs catalyst. The first model CM reactions as well as the RCM reactions have been monitored using ¹H NMR. The course of the CM reaction of 3‐phenylprop‐1‐ene ( 8 ) and cis‐1,4‐diacetoxybut‐2‐ene ( 9 ) was monitored by GC. The isomerization reaction was studied by means of GC‐mass spectrometry and in situ IR spectroscopy. All catalysts were structurally characterized by means of ¹H, ¹³C, and ³¹P NMR spectroscopy.     

(R/S)‐BINOL‐α‐Phosphoryloxy Enecarbamate‐Mediated and (R/S)‐Titanium(IV) BINOLates‐Catalyzed Enantioselective Intramolecular Heck/Aza‐Diels–Alder Cycloaddition (IHADA): An Expedient Methodology

An (R/S)‐titanium(IV) BINOLate‐catalyzed highly enantioselective intramolecular Heck/aza‐Diels–Alder cycloaddition (IHADA) cascade was developed to prepare tetrahydropyridoindoles (tHPs) and octahydropyrazinopyridoindoles (oHPPs) from in situ generated (R/S)‐BINOL α‐phosphoryloxy carbamate ( αPPC2 ) in one pot. Chiral cooperativity between (R/S)‐αPPC2 and (R/S)‐titanium(IV) BINOLate was observed and successfully utilized for the construction of various tHPs (7 examples) and oHPPs (17 examples).

     

The Catalytic Diastereo‐ and Enantioselective Claisen Rearrangement of 2‐Alkoxycarbonyl‐Substituted Allyl Vinyl Ether

The catalytic asymmetric Claisen rearrangement of 2‐alkoxycarbonyl‐substituted allyl vinyl ethers that contain two stereogenic double bonds is described. A combination of the highly Lewis acidic [Cu{(S,S)‐tert‐Bu‐box}](H₂O)₂(SbF₆)₂ complex and molecular sieves served as catalyst and afforded the Claisen rearrangement products, substituted and functionalized α‐keto esters, in high yield with a remarkable diastereo‐ and enantioselectivity. The influence of ligand structure, counterion and allyl vinyl ether double bond configuration on the stereoselectivity of the rearrangement was briefly investigated. We propose an explanation for the rate accelerating effect of the Lewis acid as well as a stereochemical model which serve to explain and predict the stereochemical course of the copper bis(oxazoline) catalyzed Claisen rearrangement.     

Synthesis,structure, and characterization of polymeric stationary phase derived from (R,R)‐tartramide and bisphenol‐S

The preparation of a new chiral polymeric stationary phase for chromatography is presented. A porous copolymer of mono‐ and dimethacrylate derivatives of bisphenol‐S and divinylbenzene containing hydroxyl functional groups was used as a matrix. (3‐Aminopropyl)triethoxysilane was used as a coupling agent and was bonded to these groups. The obtained compound was transferred into a final product during a three‐step synthesis. The properties of the obtained polymeric phase with the chiral moiety were studied. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 82: 3409–3417, 2001     

Structure and morphology of poly(β‐hydroxybutyrate) synthesized by ring‐opening polymerization of racemic (R,S)‐β‐butyrolactone with distannoxane derivatives

Predominantly syndiotactic poly((R,S)‐β‐hydroxybutyrate) (PHB) was synthesized by ring‐opening polymerization of racemic β‐butyrolactone with distannoxane derivatives as catalysts. We have studied the polymerization of (R,S)‐β‐BL using distannoxane derivatives as catalysts and the effects of polymerization time on crude yield and molecular weight of the polymers obtained. Then, a more detailed study of the characterization of polymers obtained using hydroxy‐ and ethoxy‐distannoxanes was performed. ¹³C NMR spectroscopy resolved stereosequences in synthetic PHB at the diad level for the carbonyl carbon and at the triad level for the methylene carbon. These analyses show that distannoxane catalysts produce preferentially syndiotactic polyesters (syndiotactic diads fraction from 0.56 to 0.61). Triad stereosequence distribution of PHB samples agrees favourably with the Bernoullian statistical model of chain‐end control, where ideally Φ = 4(mm) (rr)/(mr + rm)² = 1 for perfect chain‐end control. Polymer samples synthesized from distannoxane catalysts are composed of two distinct transition endotherm components with peak temperatures of approximately 42 °C and 75 °C. The formation of two melting endotherms may be due to the presence of two different crystalline structures. © 2000 Society of Chemical Industry     

Gold(I)‐Catalyzed Tandem Reaction of γ‐Amino‐Substituted Propargylic Esters to Pyrrolines and its Application in the Formal Synthesis of (±)‐Aphanorphine

An effective synthesis of structurally diverse pyrroline derivatives has been accomplished by a gold(I)‐catalyzed tandem 1,3‐acyloxy rearrangement/intramolecular azacylization reaction of γ‐amino‐substituted propargylic esters in good to excellent chemical yields (52–98%). The reaction proceeds under extremely mild conditions and has also demonstrated its potential in a concise formal synthesis of (±)‐aphanorphine with a catalyst loading as low as 0.5 mol% to provide the key intermediate 5‐(4‐methoxybenzyl)‐1‐tosyl‐2,5‐dihydro‐1H‐pyrrol‐3‐yl pivalate on a gram scale.

     

Ring‐opening metathesis polymerization of bicyclo[2.2.1]hepta‐2,5‐diene (norbornadiene) initiated by new ruthenium(II) complex

The polymerization of norbornadiene (NBD) initiated by a novel ruthenium (Ru)(II) complex ( 3 ) containing 1,1′‐pyridine‐2,6‐diylbis[3‐(dimethylamino)prop‐2‐en‐1‐one] ( 1 ) as ligand has been investigated. Ru complexes exhibit more catalytic activity in the ring‐opening metathesis polymerization (ROMP) of NBD when activated with trimethylsilyldiazomethane (TMSD). The influence of the various experimental parameters such as reaction time and temperature, nature of the solvent and catalyst, ratio of the NBD/Ru, and TMSD addition has been investigated. The polymers have been obtained in high yields with a relatively low polydispersity index for ROMP and a high $ \bar M_n $ and $ \bar M_w $ values in a monomodal distribution. Their structures have been determined by means of FTIR and ¹H‐NMR spectroscopy. Thermal properties have been determined via thermogravimetric analysis and DTG methods. The NBD polymerization results that initiated by Ru‐based catalyst coordinated to amine ligand have been compared to initiated by [RuCl₂(p‐cymene)]₂. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Catalytic Asymmetric Total Synthesis of the Muscarinic Receptor Antagonist (R)‐Tolterodine

A convenient and high yielding method for the preparation of (R)‐tolterodine, utilizing a catalytic asymmetric Me‐CBS reduction was developed. Highly enantioenriched ( R)‐6‐methyl‐4‐phenyl‐3,4‐dihydrochromen‐2‐one (94% ee) was recrystallized to yield practically enantiopure material (ee >99%) and converted to (R)‐tolterodine in a four‐step procedure. The configuration of the crucial stereocenter was preserved during the synthesis and the obtained product was identified by chiral HPLC to be the (R)‐tolterodine enantiomer.     

Synthesis of Stereodefined Substituted Cycloalkenes by a One‐Pot Catalytic Boronation–Allylation–Metathesis Sequence

Stereodefined cyclohexene and cyclopentene derivatives were prepared by the coupling of allylic alcohols and other allylic precursors with unsaturated aldehydes. These reactions are based on a multicatalytic one‐pot approach involving palladium pincer complex‐catalyzed boronation, allylation and ring‐closing metathesis reactions. This reaction sequence can be performed in an operationally simple procedure affording the cycloalkene products in high overall yields and excellent regio‐ and stereoselectivities. The presented procedure has a broad synthetic scope and high functional group tolerance, which allows the synthesis of bicyclic lactone and spirane skeletons and various substitution patterns including hydroxy, silyl, vinyl, allyl, and sulfonyl groups. The studied catalytic one‐pot reactions involve up to three individual processes performed by up to four acid‐ and transition metal‐catalyzed events.     

Biomimetic Formation of 2‐Tropolones by Dioxygenase‐Catalysed Ring Expansion of Substituted 2,4‐Cyclohexadienones

Substituted 2‐tropolone natural products are found in plants and fungi. Their biosynthesis is thought to occur by ring expansion from a cyclohexadienone precursor, but this reaction has not previously been demonstrated experimentally. Treatment of 6‐hydroxy‐6‐hydroxymethylcyclohexa‐2,4‐dienone with the non‐haem iron(II)‐dependent extradiol catechol dioxygenase MhpB from Escherichia coli results in the formation of the 2‐tropolone ring‐expansion product through a pinacol‐type rearrangement. Three further substituted cyclohexa‐2,4‐dienone analogues were prepared, and treatment of each analogue was found to give the substituted 2‐tropolone ring‐expansion product. This ring expansion could also be effected nonenzymatically by treatment with 1,4,7‐triazacyclononane and FeCl₂. This is a novel transformation for non‐haem iron‐dependent enzymes, and this is the first experimental demonstration of the proposed ring‐expansion reaction in tropolone biosynthesis.     

Practical Synthesis of (Z)‐Civetone Utilizing Ti‐Dieckmann Condensation

An efficient, practical, and stereocontrolled synthesis of (Z)‐civetone ( 1 ), a representative musk perfume, has been performed utilizing a Ti‐Dieckmann (intramolecular Ti‐Claisen) condensation of dimethyl (Z)‐9‐octadecenedioate ( 3 ) as the key step. This cyclization reaction has some advantages compared with the traditional basic Dieckmann condensation such as higher concentration (100–300 mM), lower reaction temperature (0–5 °C), shorter reaction time (1–3 h), use of environmentally benign (low toxicity and safe) reagents (TiCl₄ and Et₃N or Bu₃N), and economical reagents and solvents. 15‐, 17‐, and 19‐membered saturated β‐ketoesters ( 6–8 ) were also prepared by the present method.     

Optimization of Ring‐Closing Metathesis: Inert Gas Sparging and Microwave Irradiation

A systematic study of a ring‐closing metathesis towards a tetrasubstituted double bond as part of a seven‐membered ring in a 5.7.5‐tricyclic guaianolide system is described. By combining two techniques, namely sparging an inert gas through the solution together with dielectric heating via microwave irradiation a high‐yielding ring‐closing metathesis reaction in this particularly challenging case was achieved. The results obtained compare favorably with conventional heating conditions or with microwave irradiation in a closed system. The key aspects seem to be that rapid microwave irradiation diminishes catalyst decay by allowing the required high reaction temperature to be reached quickly and homogeneously and thereby providing enough energy for a successful metathesis reaction, while inert gas sparging is purging off evolving ethylene to shift the equilibrium to the product.