Synthese des Flechtenmakrolids (+)-Aspicilin mit Photolactonisierung als Schlüsselreaktion

Synthesis of the Lichen Macrolide (+)-Aspicilin Using Photolactonization as a Key Reaction (+)-Aspicilin, obtained from a lichen source of the Black Forest, has been proven to have the absolute configuration depicted by formula la . It is easily built up from phenol ( 14a ), 1,9-nonanediol ( 13a ), and (?)-(S-) methyloxiarane ( 6 ) (cf. Scheme 2). The latter building block provides the first stereogenic center C(17). The heterocycle is produced by photolactonization, fairly early during the course of the synthesis. The second stereogenic center is generated diastereoselectively at C(6) in compound 8 , conveniently available from photolactone 9a or 9b / 9c . Its absolute configuration depends on the kind of reducing agent and is controlled by long-range conformational transmission of chiral information. To explore the cause of stereoselection, 2D-NMR spectroscopy, X-ray structural analysis, and/or computer-aided conformational search followed by energy minimization have been used extensively, revealing the importance of the local conformation of the lactone moiety. Compound 8 , on treatment with Yamamoto's reagent, affords pre-target compound 7a almost exclusively. The latter compound, on pyridine-accelerated dihydroxylation with OsO₄, gives preferentially (+)-Aspicilin.     

Mechanistic aspects of ligand substitution on [(H2O)(tap)2RuORu(tap)2(H2O)]2+ ion {tap = 2‐(m‐tolylazo)pyridine} by some amino acids in aqueous medium at physiological pH

The interaction of the title complex with selected amino acids such as glycine (L¹H), l ‐valine (L²H), and l ‐leucine (L³H) has been studied spectrophotometrically in aqueous medium as a function of [substrate complex], [ligand], and temperature. The reaction has been monitored at 600 nm, where the spectral difference between the reactant and product is maximum. At pH 7.4, the reaction has been found to proceed via two distinct consecutive steps, i.e., it shows a nonlinear dependence on the concentration of ligands: The first process is [ligand] dependent, but the second step is [ligand] independent. The rate constants for the processes are k₁～10^?3 s^?1 and k₂～10^?4 s ^?1. The activation parameters were calculated from Eyring plots. Based on the kinetic and activation parameters, an associative interchange mechanism is proposed for the interaction processes. From the temperature dependence of the outer sphere association equilibrium constant, the thermodynamic parameters were also calculated, which gives a negative Δ G^o value for both the steps at all temperatures studied, supporting the spontaneous formation of an outer sphere association complex. The product of the reaction has been characterized with the help of conductance measurement, IR, NMR, and ESI‐mass spectroscopic analysis. © 2012 Wiley Periodicals, Inc. Int J Chem Kinet 44: 612–623, 2012     

Naphtholactam als Komplexligand

Naphtholactame as a Ligand Deprotonation of the fluorophore N‐Benz[cd]indol‐2(1H)‐on (= naphtholactame) with NaN(SiMe₃)₂ yields the naphtholactamate 1 , which is subsequently reacted with the chloro complexes [Ph₃PAuCl] and [(Ph₃P)₂PtCl₂]. The mono‐ and disubstitution products [Ph₃PAu(C₁₁H₆NO)] ( 2 ), [(Ph₃P)₂PtCl(C₁₁H₆NO)] ( 3 ) and [(Ph₃P)₂Pt(C₁₁H₆NO)₂] ( 4 ) with one ( 2 , 3 ) or two ( 4 ) metal‐N‐bonds respectively, were isolated. Substitution of chloride in the phosphanes Ph_3‐nPCl_n with 1 leads to the naphtholactamato‐N‐phosphane derivatives Ph_3‐nP(C₁₁H₆NO)_n (n = 3 ( 5 ), 2 ( 6 ), 1 ( 7 )). 7 , which is particularly sensitive towards air oxygen, is readily oxidized to give the corresponding phosphane oxide Ph₂P(O)(C₁₁H₆NO) ( 8 ). The ligating properties of 5 and 7 have been examined. In a two‐step reaction HAuCl₄, C₄H₈S (= THT) and 7 yield the phosphane complex [{Ph₂(C₁₁H₆NO)P}AuCl] ( 9 ). Photolytic activation of W(CO)₆ in THF and subsequent addition of 5 or 7 surprisingly leads to the tetracarbonyl complexes $[(CO)_{4}\overline{W\{P(C_{11}H_{6}NO)_{2}(C_{11}H_{6}NO)\}]}$/ ( 10 ) and $[(CO)_{4}\overline{W\{PPh_{2}(C_{11}H_{6}NO)\}]}$/ ( 11 ), respectively. Both exhibit a bidentate P, O‐bound naphtholactamatophosphane ligand. The compounds have been characterized by their IR‐, NMR‐ and Mass spectra, compound 11 additionally by a single crystal structure analysis. Theoretical studies on PM3‐level for 5 , including a structure optimization and as well as an NBO analysis, have been carried out.     

Enzymatic Synthesis of Amoxicillin via a One-pot Enzymatic Hydrolysis and Condensation Cascade Process in the Presence of Organic Co-solvents

A cascade reaction combining the enzymatic hydrolysis of Penicillin G potassium salt (PGK) with the kinetically controlled enzymatic coupling of in situ formed 6-aminopenicillanic acid (6-APA) with p-hydroxyphenylglycine methyl ester (D-HPGM) to give amoxicillin as the final product by using a single enzyme has been demonstrated successfully. Ethylene glycol (EG) was employed as a component of reaction buffer to improve the synthesis yield. Reaction parameters, including different cosolvents, EG content, the loading of immobilized penicillin G acylase (IPA), and reaction temperature and time were studied to evaluate their effects on the reaction. The best result of 55.2% yield was obtained from the reaction which was carried out in the mixed media containing 40% sodium dihydrogen phosphate buffer (apparent pH 6.0) and 60% EG (v/v), with the initial concentration 150 mM and 450 mM of PGK and D-HPGM, respectively, catalyzed by 50 IU/mL IPA at 25 °C for 10 h. The IPA could be recycled for nine batches without obviously losing of catalytic activity. The important strategy will have potential application in the β-lactam antibiotics industry due to the advantages of saving the effort of isolating 6-APA, reducing usual enzymatic steps and the industrial cost of amoxicillin synthesis.     

Morpholin als ambidenter Ligand

Morpholine as Ambident Ligand The reaction of MeInCl₂ with Li‐morpholinate [Li(Morph)] at 20 °C in THF gave after work‐up and recrystallization from diglyme the salt [Li(Diglyme){In₃Me₂Cl₄(Morph)₄}]·Diglyme ( 1 ). The treatment of the reaction mixture of MesInCl₂/Li(Morph) with wet THF yield as only isolated compound the coordination polymer [Li₆Cl₆(HMorph)₃] ( 2 ). Under similar conditions the reaction of InCl₃ with Li(Morph) led after work‐up in wet THF to [Li(Diglyme)₂][InCl₄(HMorph)₂] ( 3 ). 1 – 3 were characterized by NMR and IR spectroscopy as well as by X‐ray analysis. According to this, 1 contains the trinuclear anion [In₃Me₂Cl₄(Morph)₄]^? in which one of the morpholinate ligands is coordinated via N atom to the In³⁺ ions, while the O atom belongs to the coordination sphere of the Li⁺ ion. In 2 , LiCl forms a hexagonal heteroprismn, in which the morpholine molecules are responsible for a 3d network via coordination of both Lewis‐basic heteroatoms. 3 contains trans‐[InCl₄(Hmorph)₂]^? ions, connected by hydrogen bonding along [011].     

Polymergebundene Cinchonaalkaloide als Katalysatoren in der Michael Reaktion

Polymer Bound Cinchona Alkaloids as Catalysts in the Michael Reaction Three insoluble chiral polymers ( 6 , 7 and 8 ) were prepared by functionalization of copoly(styrene ?2% divinyl benzene) followed by reaction with quinine ( 9 ) or dihydrocupreine ( 10 ). Their utility as catalysts in the reaction between methyl indane-1-one-2-carboxylate ( 13 ) and 3-butene-2-one ( 14 ) was studied. Table 1 (runs 2–6 and 8) shows that the Michael-adduct 15 was formed in good chemical but low optical yields, independent of the chiral polymer used. These results are compared with those of the Michael reactions in the presence of the monomeric bases quinine ( 9 ), O-acetyl-quinine ( 11 ) and eucipine ( 12 ) (runs 1, 7 and 9).     

Carotinoide mit 7-Oxabicyclo[2.2.1]heptyl-Endgruppen. Teil I. Versuch einer Synthese von Cycloviolaxanthin (= (3S,5R,6R,3′S,5′R,6′R)-3,6:3′,6′-Diepoxy-5,6,5′,6′-tetrahydro-β,β-carotin-5,5′-diol)

Carotenoids with 7-Oxabicyclo[2,2.1]heptyl End Groups. Attempted Synthesis of Cycloviolaxanthin ( = (3S,5R,6S,3′S,5′R,6′R)-3,6:3′,6′- Diepoxy-5,6,5′,6′-tetrahydro-β,β-carotin-5,5′-diol) Starting from our recently described synthon (+)- 24 , the enantiomerically pure 3,6:4,5:3′,6′:4′,5′-tetraepoxy-4,5,4′,5′-tetrahydro-ε,ε-carotene ( 34 ) and its 15,15′-didehydro analogue 32 were synthesized in eleven and nine steps, respectively (Scheme 4). Chiroptical data show, in contrast to the parent ε,ε-carotene, a very weak interaction between the chiral centers at C(5), C(5′), C(6), C(6′), and the polyene system. Diisobutylaluminium hydride reduction of 32 lead rather than to the expected 15,15′-didehydro analogue 35 of Cycloviolaxanthin ( 8 ), to the polyenyne 36 (Scheme 5). We explain this reaction by an oxirane rearrangement leading to a cyclopropyl ether followed by a fragmentation to an aldehyd on the one side and an enol ether on the other (Scheme 6). This complex rearrangement includes a shift of the whole polyenyne chain from C(6), C(6′) to C(5), C(5′) of the original molecule.     

The Synthesis of Trimethylcyclopentane-carboxylic Acids

(1RS, 5SR)-2,2,5-Trimethylcyclopentane-1-carboxylic acid ( 17 ) and (1r, 2RS, 5SR)-1,2,5-trimethylcyclopentane-1-carboxylic acid ( 19 ) are the starting materials for the α-alkynone routes to (±)-capnellene and for similar efforts towards ptychanolide. Since 17 and 19 have, so far, been available only by a branching reaction from the same precursor, the cyanohydrin mixture 2 / 3 , a modified synthesis for 17 and a new one for 19 was developed (Scheme 1). The common precursor 2 / 3 was treated with POCl₃ which effected normal dehydration to 6 (47%, major path) in competition with Me migration to 8 and 9 (17%). The minor path to 8 and 9 could be reduced to 3% when SOCl₂ was used for the dehydration of 2 / 3 . This reaction was the basis for an improved synthesis of 17 from 1 , using the steps b, e, i, r, and v see Scheme 1 in an overall yield of 35%. The POCl₃ reaction was also studied with the pure cyanohydrins 2 and 3 , the configurations of which were determined by an X-ray analysis of 2 . Me migration did not occur form 2 but only from 3 (25%), which has HO? C(1) and H? C(5) in a cis position. With SOCl₂, 3 underwent only 5% Me migration. The new synthesis of 19 started with 4 using the steps h, n, p, and s (see Scheme 1) in an overall yield of 68%.     

Die Cope-Umlagerung als Prinzip einer repetierbaren Ringerweiterung

The Cope Rearrangement, a Reaction for Repeatable Ring Expansions Starting with the unsaturated β-ketoesters of type I, a vinyl group is introduced into the β-position by 1,4-addition of vinyl magnesium chloride to give II (Scheme 3). Treatment of the β-ketoester II with phenyl vinyl sulfoxide in the presence of sodium hydride yields the sulfoxides III, which on thermolysis lead to the α, β-divinyl ketoesters of type IV via elimination of sulfinic acid (Scheme 3). The Cope-System IV undergoes rearrangement to V, which is again an unsaturated β-ketoester. The latter is suitable for a further ring expansion sequence. These reaction steps were carried out with the nine-, twelve- and fifteen-membered ketoesters 32, 33 and 34 , as well as with the open-chain compound 35 (Table 1). With the cyclohexane derivative 31 , ring expansion could not be achieved with the described sequence.     

Theoretical study on the mechanism of extraction reaction between silylene carbene and its derivatives and thiirane

The mechanism of the sulfur extraction reaction between singlet silylene carbine and its derivatives and thiirane has been investigated with density functional theory (DFT), including geometry optimization and vibrational analysis for the involved stationary points on the potential energy surface. The energies of the different conformations are calculated by B3LYP/6-311G(d, p) method. From the potential energy profile, it can be predicted that the reaction pathway of this kind consists in two steps: (1) the two reactants firstly form an intermediate through a barrier-free exothermic reaction; (2) the intermediate then isomerizes to a product via a transition state. This kind of reactions has similar mechanism: when the silylene carbene and its derivatives [X₂Si=C: (X = H, F, Cl, CH₃)] and thiirane approach each other, the shift of 3p lone electron pair of S in thiirane to the 2p unoccupied orbital of C in X₂Si=C: gives a p → p donor-acceptor bond, thereby leading to the formation of intermediate (INT). As the p → p donor-acceptor bond continues to strengthen (that is the C-S bond continues to shorten), the intermediate (INT) generates product (P + C₂H₄) via transition state (TS). It is the substituent electronegativity that mainly affect the extraction reactions. When the substituent electronegativity is greater, the energy barrier is lower, and the reaction rate is greater.     

Approaches to the Synthesis of Cytochalasans. Part 3. Synthesis of a substituted tetrahydroisoindolinone moiety possessing the same relative configuration as proxiphomin

The total synthesis of the tetrahydroisoindolinone moiety corresponding to proxiphomin ( 1 ) is described, bearing functional groups for the attachment of the macrocyclic ring. Knoevenagel-Cope condensation of racemic 2-(benzyloxycarbonyl-amino)-3-phenylpropanal ( 2 ) with methyl (4-methyl-2,4-hexadienyl) malonate ( 3 ) yielded a mixture of the (E)- and (Z)-olefins 4a and 4b , which upon heating underwent intramolecular Diels-Alder cyclization (cf. Scheme 1). From the resulting products the tetrahydroisoindoline derivative 6 was isolated. X-ray analysis of 6 [5] revealed the same relative configurations at C(3), C(4), C(5) and C(8) as in 1 , but not at C(9). Hydrolysis of 6 with KOH was accompanied by a change in configuration at C(9) yielding the hydroxy acid 14 which was converted into the hydroxy ester 11 (cf. Scheme 4). The presence of a cis-anellated lactam ring in 11 has been confirmed by X-ray analysis of its O-acetyl derivative 16 [5]. Ring closure of the hydroxy acid 14 gave the lactone 17 , corresponding to the natural product 1 as to the configuration. The presence of the N-benzyloxycarbonyl group in lactone 6 has been shown to be essential for the above-mentioned ‘inversion’ at C(9), because no configurational change occurred with the N-unprotected lactone 8 when treated under the same conditions. The only product obtained was the hydroxy ester 10 possessing the same configuration at C(9) as 8 . Along with stereochemical considerations, mechanistic aspects of the reactions are discussed.     

A computational mechanistic study of the deamination reaction of melamine

A detailed computational study of the deamination reaction of melamine by OH^–, n H₂O/OH^–, n H₂O (where n = 1, 2, 3), and protonated melamine with H₂O, has been carried out using density functional theory and ab initio calculations. All structures were optimized at M06/6‐31G(d) level of theory, as well as with the B3LYP functional with each of the basis sets: 6‐31G(d), 6‐31 + G(d), 6‐31G(2df,p), and 6‐311++G(3df,3pd). B3LYP, M06, and ω B97XD calculations with 6‐31 + G(d,p) have also been performed. All structures were optimized at B3LYP/6‐31 + G(d,p) level of theory for deamination simulations in an aqueous medium, using both the polarizable continuum solvation model and the solvation model based on solute electron density. Composite method calculations have been conducted at G4MP2 and CBS‐QB3. Fifteen different mechanistic pathways were explored. Most pathways consisted of two key steps: formation of a tetrahedral intermediate and in the final step, an intermediate that dissociates to products via a 1,3‐proton shift. The lowest overall activation energy, 111 kJ mol^?1 at G4MP2, was obtained for the deamination of melamine with 3H₂O/OH^?.     

Halogenid‐Ionen als Katalysator: Metallzentrierte C–C‐Bindungsknüpfung ausgehend von Acetontril

Halide Ions as Catalyst: Metalcentered C–C Bond Formation Proceeded from Acetonitril AlMe₃ reacts at 20 ?C in acetonitrile to the complex [Me₃Al(NCMe)] ( 1 ). By addition of cesium halides (X^– = F^–, Cl^–, Br^–) a trimerisation to the heterocycle [Me₂Al{HNC(Me)}₂C(CN)] ( 2 ) has been observed. The reaction might be carried out under catalytic conditions (1–2 mol% CsX). The gallium complex [Me₂Ga{HNC(Me)}₂ · C(CN)] ( 3 ), generated under similar reaction conditions, can be converted to the silylated compound [Me₂Ga{Me₃SiNC(Me)}₂C(CN)] ( 4 ) by successive treatment with two equivalents n‐butyllithium and Me₃SiCl. 3 reacts under hydrolysis conditions (1 M hydrochloric acid) to the iminium salt [{H₂NC(Me)}₂C(CN)]Cl ( 5 ). A mixture of H₂O, Ph₂PCl and 3 in THF/toluene leads in a unusual conversion to the diphospane derivative [Ph₂P–P(O)(Me₂GaCl)] ( 6 ). 1 , 2 , 4 , 5 and 6 have been characterized by NMR, IR and MS techniques. X‐ray structure analyses were performed with 1 , 2 , 4 and 6 · 0.5 toluene. According this 1 possesses an almost linear axis AlNCC [Al1–N1–C3: 179,5(2)?; N1–C3–C4: 179,7(4)?]. 2 is an AlN₂C₃ six‐membered heterocycle with two iminium fuctions. One N–H group is responsible for a intermolecular chain‐formation through hydrogen bridges to an adjacent nitrile group along the direction [010]. The basic structural motif of the heterocycle 3 has been maintained after silylation to 4 . In 6 · 0.5 toluene an unit Me₂GaCl, originated from 3 , is coordinated to the oxygen atom of the diphosphane oxide Ph₂P–P(O)Ph₂.     

Asymmetric Sulfonium Ylide Mediated Cyclopropanation: Stereocontrolled Synthesis of (+)‐LY354740

The reaction of ester‐stabilized sulfonium ylides with cyclopentenone to give (+)‐ 5 ((1S,5R,6S)‐ethyl 2‐oxobicyclo[3.1.0]hexane‐6‐carboxylate), an important precursor to the pharmacologically important compound (+)‐LY354740, has been studied using chiral sulfides operating in both catalytic (sulfide, Cu(acac)₂, ethyl diazoacetate, 60 °C) and stoichiometric modes (sulfonium salt, base, room temperature). It was found that the reaction conditions employed had a major influence over both diastereo‐ and enantioselectivity. Under catalytic conditions, good enantioselectivity with low diastereoselectivity was observed, but under stoichiometric conditions low enantioselectivity with high diastereoselectivity was observed. When the stoichiometric reactions were conducted at high dilution, diastereoselectivity was reduced. This indicated that base‐mediated betaine equilibration was occurring (which is slow relative to ring closure at high dilution). Based on this model, conditions for achieving high enantioselectivity were established as follows: use of a preformed ylide, absence of base, hindered ester (to reduce ylide‐mediated betaine equilibration), and low concentration. Under these conditions high enantioselectivity (95 % ee) was achieved, albeit with low diastereocontrol. Our model for selectivity has been applied to other sulfonium ylide mediated cyclopropanation reactions and successfully accounts for the diastereoselectivity observed in all such reported reactions to date.     

Kinetic and mechanistic studies of indigocarmine oxidation by chloramine-T and chlorine in acidic buffer media

Oxidations of indigocarmine (IC) by chloramine-T (CAT) and aqueous chlorine (HOCl) in acidic buffer media, pH 2–6, have been kinetically studied at 30°C using spectrophotometry. The CAT reaction rate shows a first-order dependence on [IC]₀ and an inverse fractional order on [p-toluenesulfonamide]. The effect of [CAT] on the rate is strongly pH dependent with a variable order of 1–2 on [CAT]₀ in the pH range 6–2. The chlorine reaction rate follows first-order in [IC]₀ and [HOCl]₀ each in the pH range 6–2. Addition of halide ions and variation of ionic strength of the medium have no influence on the reaction rate. There is a negative effect of dielectric constant of the solvent. The kinetics of the IC oxidation with CAT at pH 6 and of that with HOCl at pHs 2–6 are similar suggesting similarity in their rate determining steps. A two-pathway mechanism for the CAT reaction and a one-pathway mechanism for the HOCl reaction, consistent with the kinetic data, have been proposed. Activation parameters have been calculated using the Arrhenius and Erying plots. © 1995 John Wiley & Sons, Inc.     

Theoretical study of mechanism of extraction reaction between germylene carbene and its derivatives and thiirane

The mechanism of the sulfur extraction reaction between singlet germylene carbene and its derivatives [X₂Ge?C: (X = H, F, Cl, CH₃)] and thiirane has been investigated with density functional theory, including geometry optimization and vibrational analyses for the involved stationary points on the potential energy surface. The energies of the different conformations are calculated by B3LYP/6‐311G(d,p) method. From the potential energy profile, it can be predicted that the reaction pathway of this kind consists two steps: (1) the two reactants firstly form an intermediate (INT) through a barrier‐free exothermic reaction; (2) the INT then isomerizes to a product via a transition state (TS). This kind reaction has similar mechanism, when the germylene carbene and its derivatives [X₂Ge?C: (X = H, F, Cl, CH₃)] and thiirane get close to each other, the shift of 3p lone electron pair of S in thiirane to the 2p unoccupied orbital of C in X₂Ge = C: gives a p → p donor–acceptor bond, leading to the formation of INT. As the p → p donor–acceptor bond continues to strengthen (that is the C? S bond continues to shorten), the INT generates product (P + C₂H₄) via TS. It is the substituent electronegativity that mainly affects the extraction reactions. When the substituent electronegativity is greater, the energy barrier is lower, and the reaction rate is greater. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Natural (5-oxoheptene-1E,3E-dienyl)-5,6-dihydro-2H-pyran-2-one: total synthesis and revision of its absolute configuration

The synthesis of (5^′-oxoheptene-1^′E,3^′E-dienyl)-5,6-dihydro-2H-pyran-2-one has been performed in seven steps using four key steps: a ring-closing metathesis reaction to build up the unsaturated lactone, a Wittig reaction to control the C6-C7 (E) double bond, a cross-metathesis reaction to control the (E) double bond at C8-C9, and an enantioselective allyltitanation to control the absolute configuration at C5. Spectroscopic data (IR, MS, ¹H, and ¹³C NMR) were identical to those of the natural compound except for the optical rotation, which led us to re-assign the absolute configuration of the natural product.     

Total Synthesis of the Tetracyclic Antimalarial Alkaloid (±)‐Myrioneurinol

The first total synthesis of the tetracyclic antimalarial Myrioneuron alkaloid (±)‐myrioneurinol has been accomplished using three highly diastereoselective reactions as pivotal steps: 1) an intramolecular Michael addition of a benzyloxycarbonyl‐protected lactam titanium enolate to an α,β‐unsaturated ester for construction of the spirocyclic C5 quaternary center and the a/d rings, 2) a malonate anion conjugate addition to a transient nitrosoalkene to install the requisite functionality and configuration at the C7 position, and 3) an intramolecular sulfonyliminium aza‐Sakurai reaction to form the b ring and the attendant C9/C10 configuration of the natural product.     

The Tricyclooctanone Approach to the Total Synthesis of Steroids. The Cyclization of the A-CD Unit

The first steps of a novel approach to the total synthesis of 9, 11-dehydroestrone via tricyclo[3.3.0.0^2,8]octan-3-one (2) are described. One route involves a tandem-type transformation of the key intermediate 3 (A-CD unit) consisting of cyclopropane cleavage and ring B closure to afford C, 18-bisnor-13 α, 17 α-estradiol derivatives. E.g. the 3-methoxy-9 ζ-hydroxy-17 α-methanesulfonyloxy derivative (-)- 6 has been synthesized in 8 steps and 10% overall yield from 1,3-cyclohexadiene. As an alternative, the A-CD type intermediate 4b has been prepared and could be used for a ring C enlargement prior to cyclization.