Synthesis of Glycoborine,Glybomine A and B,the Phytoalexin Carbalexin A and the β‐Adrenoreceptor Antagonists Carazolol and Carvedilol

We describe a regioselective synthesis of 4‐ or 5‐substituted carbazoles by oxidative cyclisation of meta‐oxygen‐substituted N‐phenylanilines. Using the regiodirecting effect of a pivaloyloxy group, we prepared 4‐hydroxycarbazole, a precursor for the enantiospecific synthesis of the β‐adrenoreceptor antagonists (?)‐(S)‐carazolol ( 5 ) and (?)‐(S)‐carvedilol ( 6 ). Regioselective palladium(II)‐catalysed cyclisation of different diarylamines led to total synthesis of glycoborine ( 7 ) and the first total syntheses of the phytoalexin carbalexin A ( 8 ), glybomine A ( 9 ) and glybomine B ( 10 ). For glybomine B ( 10 ), a 5‐hydroxycarbazole was converted into the corresponding triflate and utilized for introduction of a prenyl substituent.     

Enantioselective Total Synthesis of (+)‐Plumisclerin A

The first and enantioselective total synthesis of (+)‐plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring‐formation protocol was adopted to generate the characteristic tricycle[4.3.1.0^1,5]decane and trans‐fused dihyrdopyran moiety. Scalable enantioselective La^III‐catalyzed Michael reaction, palladium(0)‐catalyzed carbonylation and SmI₂‐mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D‐ring system having six continuous stereogenic centers and two all‐carbon quaternary centers. The trans‐fused dihyrdopyran moiety with an exo side‐chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)‐plumisclerin A.     

An Efficient Synthetic Strategy for Introduction of C3‐C4 Double Bond into Eudesmane Skeleton: First Total Synthesis of (+)‐Chrysanthemol

The first enantioselective synthesis of (+)‐chrysanthemol 1 was carried out starting from (+)‐dihydrocarvone in ten steps. In our studies, a facile synthetic strategy has been developed for introduction of C₃‐C₄ double bond into a eudesmane skeleton.     

Synthetic Applications of the Baylis–Hillman Reaction: Simple and Convenient Synthesis of Five Important Insect Pheromones

A simple and convenient synthesis of five important insect pheromones by means of Baylis–Hillman adducts is described, i.e., of (2E,4S)‐2,4‐dimethylhex‐2‐enoic acid ( 1 ), a mandibular‐gland secretion of the male carpenter ant in the genus Camponotus, of (+)‐(S)‐manicone ( 2 ) and (+)‐(S)‐normanicone ( 3 ), two mandibular‐gland constituents of Manica ants, and of (+)‐dominicalure‐I ( 6 ) and (+)‐dominicalure‐II ( 7 ), two aggregation pheromones of the lesser grain borer Rhyzopertha dominica (F). For the first time, the potential of the Baylis–Hillman chemistry for the stereoselective synthesis of trisubstituted olefins was successfully applied to the synthesis of these pheromone compounds.     

Synthesis and Olfactory Evaluation of (+)‐ and (−)‐γ‐Ionone

The synthesis of enantiomerically pure (+)‐ and (−)‐γ‐ionone 3 is reported. The first step in the synthesis is the diastereoisomeric enrichment of 4‐nitrobenzoate derivatives of racemic γ‐ionol 12 . The enantioselective lipase‐mediated kinetic acetylation of γ‐ionol 13b afforded the acetate 14 and the alcohol 15 , which are suitable precursors of the desired products (−)‐ and (+)‐ 3 , respectively. The olfactory evaluation of the γ‐ionone isomers shows a great difference between the two enantiomers both in fragrance response and in detection threshold. The selective reduction of (−)‐ 3 and (+)‐ 3 to the γ‐dihydroionones (−)‐(R)‐ 16 and (+)‐(S)‐ 17 , respectively, allowed us to assign unambiguously the absolute configuration of the γ‐ionones.     

Cyclisation versus 1,1‐Carboboration: Reactions of B(C6F5)3 with Propargyl Amides

A series of propargyl amides were prepared and their reactions with the Lewis acidic compound B(C₆F₅)₃ were investigated. These reactions were shown to afford novel heterocycles under mild conditions. The reaction of a variety of N‐substituted propargyl amides with B(C₆F₅)₃ led to an intramolecular oxo‐boration cyclisation reaction, which afforded the 5‐alkylidene‐4,5‐dihydrooxazolium borate species. Secondary propargyl amides gave oxazoles in B(C₆F₅)₃ mediated (catalytic) cyclisation reactions. In the special case of disubstitution adjacent to the nitrogen atom, 1,1‐carboboration is favoured as a result of the increased steric hindrance (1,3‐allylic strain) in the 5‐alkylidene‐4,5‐dihydrooxazolium borate species.     

A Facile Approach to Synthesis of the Di-O-methyl Ethers of （-）-Agatharesinol, （-）-Sugiresinol, （＋）-Nyasol and （＋）-Tetrahydronyasol

The facile enantioselective synthesis of the di-O-methyl ethers of （-）-agatharesinol （1b）, （-）-sugiresionl （2b）, （＋）-nyasol （3b） and （＋）-tetrahydronyasol （4） were achieved in high yield. The absolute configuration of （＋）-3a was confirmed via first total synthesis of （＋）-3b and （＋）-4.     

Studies towards the Synthesis of (+)-Dictyoxetane

The dolabellane-type diterpene dictyoxetane represents a significant challenge to synthetic organic chemistry. Methodology directed towards the total synthesis of naturally occurring (+)-dictyoxetane is reported. Catalytic asymmetric synthesis of the trans-hydrindane ring system is achieved through chemoselective deoxygenation of the Hajos-Parrish ketone. An alternative to the Garst-Spencer furan annulation is developed for the synthesis of a 2,5-dimethyl, tetrasubstituted furan, employing a tandem 5-exo-dig alcohol to alkyne cyclisation/aromatisation reaction as a key step. The (4+3) cycloaddition reaction of an oxyallyl cation with a tetrasubstituted furan is established on a cyclohexanone-derived model system, and a range of related (4+3) cycloadditions investigated on a homochiral, trans-hydrindane-fused furan, where regio- and diastereoselectivity is required for the natural product synthesis. In an alternative (4+2) Diels-Alder approach, a C₂-symmetric vinyl sulfoxide-based chiral ketene equivalent is used to prepare oxanorbornenes with the same oxygen bridge stereochemistry found in the 2,7-dioxatricyclo[4.2.1.0^3,8]nonane ring system of the natural product.     

σ‐Insertive Mechanism versus Concerted Non‐insertive Mechanism in the Intramolecular Hydroamination of Aminoalkenes Catalyzed by Phenoxyamine Magnesium Complexes: A Synthetic and Computational Study

The phenoxyamine magnesium complexes [{ONN}MgCH₂Ph] ( 4 a : {ONN}=2,4‐tBu₂‐6‐(CH₂NMeCH₂CH₂NMe₂)C₆H₂O^?; 4 b : {ONN}=4‐tBu‐2‐(CH₂NMeCH₂CH₂NMe₂)‐6‐(SiPh₃)C₆H₂O^?) have been prepared and investigated with respect to their catalytic activity in the intramolecular hydroamination of aminoalkenes. The sterically more shielded triphenylsilyl‐substituted complex 4 b exhibits better thermal stability and higher catalytic activity. Kinetic investigations using complex 4 b in the cyclisation of 1‐allylcyclohexyl)methylamine ( 5 b ), respectively, 2,2‐dimethylpent‐4‐en‐1‐amine ( 5 c ), reveal a first‐order rate dependence on substrate and catalyst concentration. A significant primary kinetic isotope effect of 3.9±0.2 in the cyclisation of 5 b suggests significant N?H bond disruption in the rate‐determining transition state. The stoichiometric reaction of 4 b with 5 c revealed that at least two substrate molecules are required per magnesium centre to facilitate cyclisation. The reaction mechanism was further scrutinized computationally by examination of two rivalling mechanistic pathways. One scenario involves a coordinated amine molecule assisting in a concerted non‐insertive N?C ring closure with concurrent amino proton transfer from the amine onto the olefin, effectively combining the insertion and protonolysis step to a single step. The alternative mechanistic scenario involves a reversible olefin insertion step followed by rate‐determining protonolysis. DFT reveals that a proton‐assisted concerted N?C/C?H bond‐forming pathway is energetically prohibitive in comparison to the kinetically less demanding σ‐insertive pathway (ΔΔG^≠=5.6 kcal mol^?1). Thus, the σ‐insertive pathway is likely traversed exclusively. The DFT predicted total barrier of 23.1 kcal mol^?1 (relative to the {ONN}Mg pyrrolide catalyst resting state) for magnesium?alkyl bond aminolysis matches the experimentally determined Eyring parameter (ΔG^≠=24.1(±0.6) kcal mol^?1 (298 K)) gratifyingly well.     

Total Synthesis of the Marine Sesquiterpene Quinones Hyatellaquinone and Spongiaquinone

The synthesis of the marine sesquiterpene quinone (+)‐hyatellaquinone ( 1 ) was achieved starting from the sesquiterpene aldehyde (+)‐albicanal ((+)‐ 3 ) (Schemes 3 and 4). Coupling of (+)‐albicanal with 2,3,5,6‐tetramethoxyphenyllithium led to the aryl‐sesquiterpene system, which was modified to the target molecule. Furthermore, the first total synthesis of the marine compound spongiaquinone ( 2 ) was carried out starting from ((?)‐albicanal (?)‐ 3 ) in a reaction sequence encompassing a stereoselective C?C bond hydrogenation and a one‐pot AcOH elimination/demethylation reaction (Schemes 7 and 10). The occurrence of 1,2‐ and 1,4‐benzoquinone forms of 1 and 2 depends on the pH of the solvent system.     

Double Catalytic Kinetic Resolution (DoCKR) of Acyclic anti‐1,3‐Diols: The Additive Horeau Amplification

The concept of a synergistic double catalytic kinetic resolution (DoCKR) as described in this article was successfully applied to racemic acyclic anti ‐1,3‐diols, a common motif in natural products. This process takes advantage of an additive Horeau amplification involving two successive enantioselective organocatalytic acylation reactions, and leads to diesters and recovered diols with high enantiopurities. It was first developed with C ₂‐symmetrical diols and then further extended to non‐C ₂‐symmetrical anti diols to prepare useful chiral building blocks. The protocol is highly practical as it only requires 1 mol % of a commercially available organocatalyst and leads to easily separable products. This procedure was applied to the shortest reported total synthesis of (+)‐cryptocaryalactone, a natural product with anti‐germinative activity.     

Total Synthesis of (+)‐Cornexistin

Herein, we describe the first total synthesis of (+)‐cornexistin as well as its 8‐epi‐isomer starting from malic acid. The robust and scalable route features a Nozaki–Hiyama–Kishi reaction, an auxiliary‐controlled syn‐Evans‐aldol reaction, and a highly efficient intramolecular alkylation to form the nine‐membered carbocycle. The delicate maleic anhydride moiety of the nonadride skeleton was constructed from a β‐keto nitrile. The developed route enabled the synthesis of 165 mg (+)‐cornexistin.     

On the synergistic catalytic properties of bimetallic mesoporous materials containing aluminum and zirconium: the Prins cyclisation of citronellal

Bimetallic three‐dimensional amorphous mesoporous materials, Al‐Zr‐TUD‐1 materials, were synthesised by using a surfactant‐free, one‐pot procedure employing triethanolamine (TEA) as a complexing reagent. The amount of aluminium and zirconium was varied in order to study the effect of these metals on the Brønsted and Lewis acidity, as well as on the resulting catalytic activity of the material. The materials were characterised by various techniques, including elemental analysis, X‐ray diffraction, high‐resolution TEM, N₂ physisorption, temperature‐programmed desorption (TPD) of NH₃, and ²⁷Al MAS NMR, XPS and FT‐IR spectroscopy using pyridine and CO as probe molecules. Al‐Zr‐TUD‐1 materials are mesoporous with surface areas ranging from 700–900 m² g^?1, an average pore size of around 4 nm and a pore volume of around 0.70 cm³ g^?1. The synthesised Al‐Zr‐TUD‐1 materials were tested as catalyst materials in the Lewis acid catalysed Meerwein–Ponndorf–Verley reduction of 4‐tert‐butylcyclohexanone, the intermolecular Prins synthesis of nopol and in the intramolecular Prins cyclisation of citronellal. Although Al‐Zr‐TUD‐1 catalysts possess a lower amount of acid sites than their monometallic counterparts, according to TPD of NH₃, these materials outperformed those of the monometallic Al‐TUD‐1 as well as Zr‐TUD‐1 in the Prins cyclisation of citronellal. This proves the existence of synergistic properties of Al‐Zr‐TUD‐1. Due to the intramolecular nature of the Prins cyclisation of citronellal, the hydrophilic surface of the catalyst as well as the presence of both Brønsted and Lewis acid sites synergy could be obtained with bimetallic Al‐Zr‐TUD‐1. Besides spectroscopic investigation of the active sites of the catalyst material a thorough testing of the catalyst in different types of reactions is crucial in identifying its specific active sites.     

Enantioselective Synthesis of Arene cis‐Dihydrodiols from 2‐Pyrones

An enantioselective chemical synthesis of arene cis‐dihydrodiols has been realized from 2‐pyrones through sequential ytterbium‐catalyzed asymmetric inverse‐electron‐demand Diels–Alder (IEDDA) reaction of 2‐pyrones and retro‐Diels–Alder extrusion of CO₂. By using this strategy, a series of substituted arene cis‐dihydrodiols can be obtained efficiently with high enantioselectivity (>99 % ee in many cases). Based on this strategy, efficient and concise asymmetric total syntheses of (+)‐MK7607 and 1‐epi‐(+)‐MK7607 were accomplished.     

Chiral M3L2 Self‐Assembled Capsules through Metal Coordination of Enantiopure Ligating Benzocyclotrimers: NMR Spectroscopic and ESI Mass Spectrometric Investigation

The synthesis of enantiopure (+)‐benzotricamphor syn‐ 5 , an important chiral C₃‐symmetric rigid building block for supramolecular applications, was studied in detail to reduce the number of steps and to increase the diastereoselectivity and overall yield. The new synthetic procedure allowed larger amounts of syn‐ 5 to be obtained and used for the preparation of new derivatives, such as the corresponding tris‐trifluoromethanesulfonate syn‐ 12 , which was efficiently transformed into (+)‐benzotribornenetrinitrile syn‐ 1 and (+)‐benzotribornenetris(ethynyl‐4‐pyridine) syn‐ 2 . The previously reported (+)‐benzotricamphortrioxime syn‐ 6 was transformed into tris‐nitrile syn‐ 3 by Beckman reaction. Compounds syn‐ 1 – 3 were employed as multidentate ligands for silver(I) and platinum(II) centres in apolar solvents. The linear coordination geometry of Ag^I and square‐planar geometry of cis‐chelated Pt^II in combination with the chiral tripodal ligands syn‐ 1 – 3 led to the formation of chiral enantiopure capsules with M₃L₂ stoichiometry, as confirmed by 2D NMR NOESY and DOSY experiments as well as ESI mass spectrometry.     

AN EFFICIENT SYNTHESIS OF 1,4-OXAZEPINES FROM β-FORMYL ENAMIDE USING I2-NaHCO3 SYSTEM

A new and efficient method for synthesis of 1,4-oxazepine has been developed utilizing I₂-NaHCO₃ promoted intramolecular cyclisation of N-progargyl-β-hydroxylmethyl enamide. The method is mild and simple.     

Synthesis of (+)-(4S, 8R)hyphen;8hyphen;Epi- and (−)-(4R, 8S)-4-Epi-β-bisabolol

The first total enantioselective synthesis of (+)-(4S, 8R)-8-epi-β-bisabolol(+)- 1 and of (?)-(4R, 8 S )-4-epi-β-bisabolol ((?))? 1 ) is reported. The key step in the synthesis is the kinetic resolution of (±)? 5 by means of the Sharpless epoxidation yielding (?)- and (+}? 6 , respectively. Reduction of the epoxides with LiAlH₄ gave the diols (+)-and(?)? 7 which were transformed into (+)- and (?)? 8 , respectively, via the corresponding mesylate. Reaction of these epoxides with the Grignard reagent derived from homoprenylbromide, assisted by Li₂CuCl₄, finished the synthesis of the target compounds 1 with high diastereo- and enantioselectivity.     

Synthesis of Benzimidazoles by Phosphine‐Mediated Reductive Cyclisation of ortho‐Nitro‐anilides

Heating ortho‐nitro‐anilides 1 – 3 and 2‐methyl‐N‐(3‐nitropyridin‐2‐yl)propanamide ( 5 ) with 4 equiv. of a phosphine led to the 2‐substituted benzimidazoles 6 – 8 and to the imidazo[4,5‐b]pyridine 10 , respectively, in yields between 45 and 85%. Heating 1 with (EtO)₃P effected cyclisation and N‐ethylation, leading to the 1‐ethylbenzimidazole 6b . The slow cyclisation of the N‐pivaloylnitroaniline 2b allowed isolation of the intermediate phosphine imide 11 that slowly transformed into the 1H‐benzimidazole 7b . The structure of 11 was established by crystal‐structure analysis. While the N‐methylated ortho‐nitroacetanilide 3 cyclised to the 1,2‐dimethyl‐1H‐benzimidazole ( 8 ), the 2‐methylpropananilide 4 was transformed into 1‐methyl‐3‐(1‐methylethyl)‐2H‐benzimidazol‐2‐one ( 9 ).     

Enzyme‐Mediated Preparation of (+)‐ and (−)‐β‐Irone and (+)‐ and (−)‐cis‐γ‐Irone from Irone alpha®

The (−)‐ and (+)‐β‐irones ((−)‐ and (+)‐ 2 , resp.), contaminated with ca. 7 – 9% of the (+)‐ and (−)‐trans‐α‐isomer, respectively, were obtained from racemic α‐irone via the 2,6‐trans‐epoxide (±)‐ 4 (Scheme 2). Relevant steps in the sequence were the LiAlH₄ reduction of the latter, to provide the diastereoisomeric‐4,5‐dihydro‐5‐hydroxy‐trans‐α‐irols (±)‐ 6 and (±)‐ 7 , resolved into the enantiomers by lipase‐PS‐mediated acetylation with vinyl acetate. The enantiomerically pure allylic acetate esters (+)‐ and (−)‐ 8 and (+)‐ and (−)‐ 9 , upon treatment with POCl₃/pyridine, were converted to the β‐irol acetate derivatives (+)‐ and (−)‐ 10 , and (+)‐ and (−)‐ 11 , respectively, eventually providing the desired ketones (+)‐ and (−)‐ 2 by base hydrolysis and MnO₂ oxidation. The 2,6‐cis‐epoxide (±)‐ 5 provided the 4,5‐dihydro‐4‐hydroxy‐cis‐α‐irols (±)‐ 13 and (±)‐ 14 in a 3 : 1 mixture with the isomeric 5‐hydroxy derivatives (±)‐ 15 and (±)‐ 16 on hydride treatment (Scheme 1). The POCl₃/pyridine treatment of the enantiomerically pure allylic acetate esters, obtained by enzymic resolution of (±)‐ 13 and (±)‐ 14 , provided enantiomerically pure cis‐α‐irol acetate esters, from which ketones (+)‐ and (−)‐ 22 were prepared (Scheme 4). The same materials were obtained from the (9S) alcohols (+)‐ 13 and (−)‐ 14 , treated first with MnO₂, then with POCl₃/pyridine (Scheme 4). Conversely, the dehydration with POCl₃/pyridine of the enantiomerically pure 2,6‐cis‐5‐hydroxy derivatives obtained from (±)‐ 15 and (±)‐ 16 gave rise to a mixture in which the γ‐irol acetates 25a and 25b and 26a and 26b prevailed over the α‐ and β‐isomers (Scheme 5). The (+)‐ and (−)‐cis‐γ‐irones ((+)‐ and (−)‐ 3 , resp.) were obtained from the latter mixture by a sequence involving as the key step the photochemical isomerization of the α‐double bond to the γ‐double bond. External panel olfactory evaluation assigned to (+)‐β‐irone ((+)‐ 2 ) and to (−)‐cis‐γ‐irone ((−)‐ 3 ) the strongest character and the possibility to be used as dry‐down note.     

A Concise and Highly Enantioselective Total Synthesis of (+)‐anti‐ and (−)‐syn‐Mefloquine Hydrochloride: Definitive Absolute Stereochemical Assignment of the Mefloquines

A concise asymmetric (>99:1 e.r.) total synthesis of (+)‐anti‐ and (?)‐syn‐mefloquine hydrochloride from a common intermediate is described. The key asymmetric transformation is a Sharpless dihydroxylation of an olefin that is accessed in three steps from commercially available materials. The Sharpless‐derived diol is converted into either a trans or cis epoxide, and these are subsequently converted into (+)‐anti‐ and (?)‐syn‐mefloquine, respectively. The synthetic (+)‐anti‐ and (?)‐syn‐mefloquine samples were derivatized with (S)‐(+)‐mandelic acid tert‐butyldimethylsilyl ether, and a crystal structure of each derivative was obtained. These are the first X‐ray structures for mefloquine derivatives that were obtained by coupling to a known chiral, nonracemic compound, and provide definitive confirmation of the absolute stereochemistry of (+)‐anti‐ as well as (?)‐syn‐mefloquine.