Stereoselective total synthesis of almorexant

A highly stereoselective synthesis of almorexant has been achieved using (R)-tert-butanesulfinamide as a chiral source. The chiral tetrahydroisoquinoline core was constructed through allylation of chiral N-sulfinyl imine followed by ring closure of the secondary amide with a tethered halide. The chiral α-phenyl amide was introduced by means of S_N2 substitution of (S)-methyl 2-phenyl-2-(tosyloxy)acetate with chiral tetrahydroisoquinoline.     

Total synthesis of (±)-xanthocidin using FeCl3-mediated Nazarov reaction

The total synthesis of the antibiotic, (±)-xanthocidin (1), is described. The FeCl₃-promoted fast Nazarov reaction of the β-alkoxy divinyl ketone in the presence of t-BuOH provided the α-exo-methylene cyclopentenone, which is the core skeleton of this natural product. After methoxymethyl (MOM) esterification and protection of the reactive exo-methylene unit with a phenylseleno group, dihydroxylation, followed by oxidation, gave xanthocidin MOM ester. Finally, this ester was converted into (±)-xanthocidin (1) under mild conditions.     

A kinetic ESR study of the reaction of t-butylperoxy radicals with hexaphenylditin and hexaphenyldilead

Absolute rate constants for the reaction of t-butylperoxy radicals with hexaphenylditin and hexaphenyldilead have been found to fit the equations log (k_p/M⁻¹·s⁻¹) = (5.5±0.15) − (3800±150)/Θ and log (k_p/M⁻¹·s⁻¹) (9.5±0.3) − (6000±250)/Θ, where Θ = 2.303 RT cal mol⁻¹, respectively.     

Synthesis of (±)-phthalascidin 650 analogue: new synthetic route to (±)-phthalascidin 622

A synthesis of functionalized phenolic α-amino-alcohol (±)-13 as synthetic precursor of the catechol tetrahydroisoquinoline structure of phthalascidin 650 is disclosed. Starting from 3-methylcatechol 5, eight steps of synthesis give rise to the synthesis of phenolic α-amino-alcohol (±)-13 in 27% overall yield. This synthetic strategy involves the elaboration of fully functionalized aromatic aldehyde 8 and its transformation into a phenolic α-amino-alcohol (±)-13, through a Knoevenagel condensation, simultaneous reduction of nitroketene and ester functions and hydrogenolysis of the benzyl protecting group. The pentacycle (±)-18 was obtained after four additional steps. The Pictet-Spengler cyclisation between the phenolic α-amino-alcohol (±)-13 and N-protected α-amino-aldehyde 4 allowed to obtain (1,3′)-bis-tetrahydroisoquinoline 14 with N-methylated and N-Fmoc removed. The last step was a Swern oxidation for allowing an intramolecular condensation.     

New practical access to 2-azatryptophans and dehydro derivatives via the Wittig-Horner reaction

The Wittig-Horner reaction of protected 3-formylindazoles 1 with (±)-N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester 2 has been developed as a new practical synthesis of dehydro 2-azatryptophans and amino acid derivatives. The preparation of 5-bromo-3-formylindazole is discussed.     

Ligand exchange reaction of Zn(II)-acetylacetonate complex with 5,10,15,20-tetraphenyl-21H,23H-porphinetetrasulfonic acid

Ligand exchange reaction of Zn(II)-acetylacetonate complex (Zn-acac₂) with 5,10,15,20-tetraphenyl-21H,23H-porphinetetrasulfonic acid (H₂TPPS) has been investigated spectrophotometrically and radiometrically. The exchange reaction was observed by spectral change from H₂TPPS to Zn-TPPS or activity of⁶⁵Zn(acac)₂ extracted into the chloroform phase. The 2nd order rate constants (k ₂) for the exchange reaction at 70 °C and at pH 7.8 were found to be 32.8±2.3 and 31.2±3.2 M^–1·s^–1 from the spectrometric and radiotracer experiments, respectively. For the direct complexation of Zn(II) with H₂TPPS, a similar 2nd order rate constant (k=32.4±4.7 M^–1·s^–1) was obtained as that in the ligand exchange reaction. The activation energies (E) for the exchange and the formation of Zn-TPPS were found to be 69.3±0.2 and 69.4±0.2 kJ·mol^–1, respectively, in the temperature range from 40 to 70 °C.     

Total synthesis of (±)-brazilin and formal synthesis of (±)-brazilein, (±)-brazilide A using m-CPBA

Total synthesis of (±)-brazilin has been accomplished. m-CPBA epoxidation of allyl alcohol 10 and epoxy opening reaction mediated by m-chlorobenzoic acid, formed in situ as a byproduct, gave advanced intermediate diol 14. O-alkylation and cyclization gave phenol 6 which enabled the formal synthesis of (±)-brazilein and (±)-brazilide A.     

Stereoselective synthesis of tetrahydroisoquinoline alkaloids: (−)-trolline, (+)-crispin A, (+)-oleracein E

Tetrahydroisoquinoline alkaloids, (S)-(−)-trolline, (R)-(+)-crispin A, and (R)-(+)-oleracein E, have been synthesized stereoselectively from the both enantiomers of common intermediate (S)-4 and (R)-4. The key step in the synthesis include a stereoselective Bi(OTf)₃-catalyzed intramolecular 1,3-chirality transfer reaction of chiral non-racemic amino allylic alcohols (S)-6 and (R)-6 to construct both enantiomers of (E)-1-propenyl tetrahydroisoquinoline 4.     

Synthesis of tetrahydroisoquinoline-diamine ligands and their application in asymmetric transfer hydrogenation

The use of the tetrahydroisoquinoline scaffold is well documented in biologically active compounds. However, reports of the utilisation of tetrahydroisoquinoline compounds in asymmetric catalysis are limited. The synthesis of novel diamine ligands possessing the tetrahydroisoquinoline (tetrahydroisoquinoline) backbone and evaluation of their activity in the asymmetric transfer hydrogenation of acetophenone are presented. The diamine ligands in conjunction with i-PrOH as the hydrogen source and [RhCl₂(Cp1)]₂ as the metal precursor proved to be the most effective of the tetrahydroisoquinoline derivatives for this catalytic system. Water was found to have a profound influence on the enantioselectivity of the reaction. Optimisation of the amount water, i-PrOH and catalytic loading content rendered the best result of 70% enantioselectivity for the (S)-1-phenylethanol isomer product.     

Visible light mediated photocatalytic oxidative coupling reaction of N-phenyl tetrahydroisoquinoline with β-keto acids

A visible light mediated photocatalytic oxidative coupling reaction of N-phenyl tetrahydroisoquinoline with β-keto acids has been developed. This approach provides a mild and operationally simple access to the synthesis of C1-acylmethylated tetrahydroisoquinolines.     

The first total synthesis of (±)-zenkequinone B

The first total synthesis of tetrahydrobenzo[a]anthraquinone natural product (±)-zenkequinone B (1) is reported. The key step involves the TiCl₄-promoted intramolecular cyclization of 4-aryl-2-hydroxybutanal diethyl acetal 4 to give compound 3. The total synthesis of (±)-zenekequinone B (1) has been accomplished in five steps from readily available 2-(chloromethyl)-9,10-dimethoxyanthracene (5) in 40.3% overall yield.     

Total synthesis of (±)-stemonamide, (±)-isostemonamide, (±)-stemonamine, and (±)-isostemonamine using a radical cascade

A total synthesis of (±)-stemonamide and (±)-isostemonamide has been achieved by using a radical cascade that involves two endo-selective cyclizations. (±)-Stemonamine and (±)-isostemonamine are synthesized by chemoselective reduction of (±)-stemonamide and (±)-isostemonamide, respectively.     

New optically active organoantimony (BINASb) and bismuth (BINABi) compounds comprising a 1,1′-binaphthyl core: synthesis and their use in transition metal-catalyzed asymmetric hydrosilylation of ketones

Racemic 2,2′-bis[diarylstibano]-1,1′-binaphthyls [(±)-BINASbs] and 2,2′-bis[di(p-tolyl)bismuthano]-1,1′-binaphthyl [(±)-BINABi], which are the antimony and bismuth congeners of BINAP, have been prepared from 2,2′-dibromo-1,1′-binaphthyl (DBBN) via 2,2′-dilithio-1,1′-binaphthyl intermediate by treatment with the appropriate metal halides [(p-Tol)₂SbBr, Ph₂SbBr and (p-Tol)₂BiCl]. The optical resolution of the (±)-BINASbs could be achieved via the separation of a mixture of the diastereomeric Pd-complexes derived from the reaction of (±)-BINASbs with di-μ-chlorobis{(S)-2-[1-(dimethylamino)-ethyl]phenyl-C¹,N}dipalladium(II). Optically active (R)-BINASb and (R)-BINABi could be also obtained from optically active (R)-DBBN by the same procedure. The enantiopure BINASbs have been shown to be effective chiral ligands for the rhodium-catalyzed asymmetric hydrosilylation of ketones.     

Synthesis of a new bluish pigment from the reaction of a methylpyranoanthocyanin with sinapaldehyde

The synthesis of a new pigment with a bluish color was obtained from the reaction of methylpyranomalvidin-3-glucoside with sinapaldehyde and its formation mechanism seems to involve a charge-transfer reaction pathway. The structure of this compound was fully characterized by LC/DAD-MS and NMR. Its equilibrium forms present in water at different pH values and the respective ionization constants were determined by UV-visible spectroscopy. The results revealed the presence of three equilibria involving only deprotonation reactions at the 7-OH and 4′-OH positions of the pyranoanthocyanin moiety and at the 4′″-OH of the syringol moiety (pK_a1 = 3.64 ± 0.01; pK_a2 = 8.02 ± 0.01; pK_a3 = 11.19 ± 0.01).     

B(C6F5)3: an efficient catalyst for reductive alkylation of alkoxy benzenes and for synthesis of triarylmethanes using aldehydes

Tris(pentafluorophenyl)borane [B(C₆F₅)₃] has been used as an efficient catalyst for reductive alkylation of alkoxy benzenes using aldehydes as an alkylating agent in the presence of polymethylhydrosiloxane (PMHS). Various alkylated trimethoxybenzene derivatives have been prepared in good to high yields. In addition, B(C₆F₅)₃ was also used as a catalyst for the reaction of electron-rich arenes with aldehydes to obtain triarylmethanes. The use of reductive alkylation protocol for the synthesis of an isochroman and tetrahydroisoquinoline derivatives has also been demonstrated.     

First example of an Ugi type reaction on phenylsulfinimine-avermectin B1 derivatives

A short synthesis of 4″-(S)-4″-deoxy-4″-trifluoroacetylamino-4″-alkylcarbamoyl-avermectin B₁4 has been developed through the diastereoselective Ugi reaction to an phenylsulfinimide intermediate.     

Formal synthesis of (±)-brazilin and total synthesis of (±)-brazilane

A convergent synthesis towards (±)-brazilin and (±)-brazilane has been reported from 3,4-dimethoxy benzaldehyde in <15 reaction steps. Palladium(II)-catalysed intramolecular Friedel–Crafts cyclisation and Lewis acid supported intermolecular Friedel–Crafts alkylation reactions have been demonstrated. A tetracyclic substituted indane common key intermediate is employed to furnish the desired two molecules in good to excellent yield. Pd(OH)₂ has played a crucial role in the total synthesis of (±)-brazilane.     

Chemo-enzymatic short-step total synthesis of symbioramide

A concise synthesis of symbioramide, a marine-origin ceramide from a common starting material, methyl (±)-trans-2,3-epoxyoctadecanoate, in a convergent manner was achieved. The key step is the direct lipase-catalyzed coupling reaction between methyl (2R,3E)-2-hydroxy-3-octadecenoate and non-protected (±)-erythro-dihydrosphingosine, giving natural (2S,3R,2′R)-symbioramide and its (2R,3S,2′R)-isomer in 38% and 37% yield, respectively. The optically active β,γ-unsaturated α-hydroxyester was prepared by Mg(ClO₄)₂-mediated isomerization of epoxide and the subsequent lipase PS-catalyzed kinetic resolution.     

Kinetic investigation of a PC(sp)P pincer palladium (II) complex in the Heck reaction

An investigation of the kinetics of the Heck reaction between 4-iodoanisole and styrene catalysed by {cis-1,3-bis[(di-tert-butylphosphino)methyl]-cyclohexane} palladium (II) iodide (1) has been performed in DMF-d₇ solution. Based on mercury poisoning experiments a heterogeneous palladium catalyst formed from the pre-catalyst is proposed. Saturation behaviour with respect to the olefin concentration suggests a mechanism consisting of a pre-equilibrium association of the olefin followed by a rate determining reaction with aryl halide. The equilibrium constant for the olefin association, K₁, and the rate constant for the subsequent oxidative addition step, k₂, were determined to (5.7 ± 2.5) × 10⁻³ and 18.4 ± 2.7 M⁻¹ s⁻¹, respectively.     

Novel total syntheses of (±)-oxerine by intramolecular Heck reaction

Both a three-step and a five-step syntheses of monoterpene alkaloid (±)-oxerine from alcohol 6 have been accomplished. In the second approach, the synthetic efficiency was enhanced by implementing a one-pot protocol (deprotonation/silylation/ alkylation/desilylation). The construction of the cyclopenta[c]pyridine framework was realized by an intramolecular Heck reaction, which should be adaptable for the synthesis of other related monoterpene pyridine alkaloids.