On Cardioactive Steroids. VIII. The Synthesis of Bufalin and Resibufogenin Isomers

α-Isobufalin

1 Systematic names are given at the titles of the Exper. Part.

( 1 ) and β-isoresibufogenin ( 3 ) have been synthesized from testosterone by a method which features a novel oxidative furan to pyrone transformation.     

Synthesis,Structure, and Redox Chemistry of a Vitamin-B12s-Related Macrocyclic Complex of Cobalt(I)

(±)-[1-hydro-8H-HDP]cobalt(I) 1

1 Full name of 1: [2,2,3,3,7,7,8,8,12,12,13,13,17,17,18,18,-hexadecamethyl-2,3,7,8,12,13,17,18,-octahydro-1H,23H-10,20-diaza-porphinato]cobalt(I); full name of 2a : dibromo[2,2,3,3,7,7,8,8,12,12,13,13,17,17,18,18-hexadecamethyl-2,3,7,8,12,13,17,18-octahydro-1H,21H-10,20-diazaporphinato]cobalt(III).

2 For the nomenclature of [HDP]-complexes see addendum in [2].

is obtained by chemical or electrochemical four-electron reduction of (±)-dibromo- or (±)-dicano[1-hydroxy-8H-HDP]cobalt(III) 2a or 2b ⁴, respectively. The crystal nad molecular structure of 1 was determined by combination of X-ray analysis and MS, ¹H-, and ¹³C-NMR spectroscopy. Square-planar coordinated Co(I) lies closely to the best plane through the four N-atoms which form the first coordination sphere. Thermodynamic data for the coordination of axial bases with the cation of [1-hydroxy-8H-HDP]cobalt 2 in its different metal oxidation states were determined. The pathway of the overall four-electron reduction of 2a to 1 was elucidated: it involves a two-electron reduction of the central metal, a two-electron reduction of the macrocycle accompanied by elimination of the OH-group and final protonation at C(1). Evidence for an intramolecular electron transfer between the central metal and the macrocycle is presented.     

Umsetzungen von 1,3-Thiazol-5(4H)-thionen mit Grignard- und Organolithium-Verbindungen: Carbophile und Thiophile Additionen

Reactions of 1,3-Thiazole-5(4H)-thiones with Grignard- and Organolithium Compounds: Carbophilic and Thiophilic Additions Organolithium compounds and 1,3-thiazole-5(4H)-thiones 9 reacted via thiophilic addition on the exocyclic S-atom. The intermediate anion E has been trapped by protonation to give 12 and by alkylation to yield 16 , respectively (Schemes 5 and 6). In competition with protonation of E , a fragmentation to benzonitrile and a dithioester 14 was observed (Scheme 5). In some cases, the alkylation of E led to the formation of dithioacetals 17 instead of 16 (Scheme 6). Methyl, ethyl, and isopropyl Grignard reagents and 9 in THF underwent again a thiophilic addition yielding 4,5-dihydro-1,3-thiazoles of type 12 (Scheme 3). In contrast to this result, MeMgI reacted with 9a in Et₂O via carbophilic addition to 11 . Again a carbophilic attack at C(5) of 9 was observed with allylmagnesium and 2-propynylmagnesium bromide, respectively, in Et₂O.     

Synthesis of potential ambra odorants: 5,5,9-trimethyldecalyl derivatives

The synthesis of racemic stereoisomeric compounds with the 5,5,9-trimethyldecalin skeleton and an oxygen function at C(1), C(2), or C(3) is described

1 Although racemic decalins are described, only the enantiomer related to steroids is drawn. The projection of the decalins was chosen so as to place the angular methyl group above the plane of the molecule and the oxygen function at C(1), C(2) or C(3) on the left side, as represented by formula 1–6 . The relative configuration of the substituents in decalins is designated by using the convention of the steroid series: β, meaning on the same side as the angular methyl group at C(9) and α, meaning on the side opposite from the angular methyl group. The prefix cis or trans refers to the fusion of the decalin ring system, not to the position of the substituents.

. A novel general one-step synthesis of 2-decalones by means of acid catalyzed cyclization of acyclic or monocyclic precursors has been developed.     

Nickel-catalyzed Asymmetric Alkylation of Some Chiral and Achiral Allylic Alcohols. Preliminary communication

[(?) (R)-1,2-bis (Diphenylphosphino)-1-phenylethane]nickel (II) chloride was found to catalyze the asymmetric alkylation of some chiral and achiral allylic alcohols with Grignard reagents, leading to the formation of optically active olefins. Enantiomer discrimination of the substrate takes place in the alkylation of chiral allylic alcohols.     

Nukleophile Alkylierung aromatischer Nitroverbindungen

Nucleophilic alkylation of aromatic nitro compounds Aromatic nitro compounds may be alkylated in o- or p-position by treatment with alkyl lithium or alkyl Grignard reagents.     

The Conquest of Taxol

Much has been written about taxol, one of the newest weapons against cancer, and its producer, the Pacific Yew tree (Taxus brevifolia).

1 K. C. Nicolaou, W.-M. Dai, R. K. Guy, Angew. Chem. 1994, 106, 38–69; Angew. Chem. Int. Ed. Engl. 1994, 33, 15–44.

In this article, the authors give a frank and behind-the-scenes account of their encounter with this well-known molecule, which they and their collaborators faced as a synthetic target.

2 K. C. Nicolaou, Z. Yang, J.-J. Liu, H. Ueno, P. G. Nantermet, R. K. Guy, C. F. Claiborne, J. Renaud, E. A. Couladouros, K. Paulvannan, E. J. Sorensen, Nature (London) 1994, 367, 630–634.

3 K. C. Nicolaou, J.-J. Liu, Z. Yang, H. Ueno, R. K. Guy, E. A. Couladouros, E. J. Sorensen, J. Am. Chem. Soc. 1995, 117, 624–633.

4 K. C. Nicolaou, J.-J. Liu, Z. Yang, H. Ueno, E. J. Sorensen, C. F. Claiborne, R. K. Guy, C.-K. Hwang, M. Nakada, P. G. Nantermet, J. Am. Chem. Soc. 1995, 117, 634–644.

5 K. C. Nicolaou, Z. Yang, J.-J. Liu, P. G. Nantermet, C. F. Claiborne, J. Renaud, R. K. Guy, K. Shibayama, J. Am. Chem. Soc. 1995, 117, 645–652.

6 K. C. Nicolaou, H. Ueno, J.-J. Liu, P. G. Nantermet, Z. Yang, J. Renaud, K. Paulvannan, R. Chadha, J. Am. Chem. Soc. 1995, 117, 653–659.

Once again total synthesis is found to offer excellent opportunities for developing new synthetic strategies and novel reactions. The team of chemists who took up this challenge emerged with valuable experience and confidence in their skills.     

Radikalische Cyclisierungen von Alkenyl-substituierten 4,5-Dihydro-1,3-thiazol-5-thiolen

Radical Cyclizations of Alkenyl-Substituted 4,5-Dihydro-1,3-thiazole-5-thiols Heating of 5-alkenyl- or 5-alkinyl-4,5-dihydro-1,3-thiazole-5-thiols of type 5 in the presence of a radical initiator gave dithiaspirobicycles in fair-to-excellent yield (Scheme 3). Under analogous conditions, the 4,5-dihydro-4-vinyl-1,3-thiazole-5-thiol 5d underwent a cyclization to give the annellated dithiabicycle 7 (Scheme 4). In this reaction, a minor product 8 was formed by an unknown reaction mechanism. The structure of 8 was established by X-ray crystallography. The starting 1,3-thiazole-5-thiols 5 have been synthesized by carbophilic alkylation of me C?S group of 1,3-thiazole-5(4H)-thiones with Grignard-reagents or alkylcuprates. The thiazolethiones were obtained by the reaction of 3-amino-2H-azirines with thiobenzoic acid followed by sulfurization and cyclization. The 4-benzyl derivative 1b was thermally rearranged via 1,3-benzyl migration to yield the benzyl (1,3-thiazol-5-yl) sulfide 11 (Scheme 5).     

Ethylene-Octene Copolymer-Nanosilica Nanocomposites: Effects of Epoxy Resin Functionalized Nanosilica on Morphology,Mechanical, Dynamic Mechanical and Thermal Properties

A comparative study of the structural, thermal, mechanical and thermomechanical properties of ethylene-octene copolymer 1

1 Ethylene-octene copolymer is produced using Dow's INSITETM ™ constrained geometry catalyst and process technology. ENGAGE the trade name of this copolymer.

(mPE) 2

2 This copolymer will be represented as mPE .

nanocomposites synthesized with pure nanosilica (NS) and nanosilica-functionalized with diglycidyl ether of bisphenol-A (ENS) has been reported. These nanocomposites were prepared using “melt mixing” method at a constant loading level of 2.5 wt. %. The effects of pure nanosilica (NS) and epoxy resin-functionalized-nanosilica (ENS) on the above mentioned properties of ethylene-octene copolymer were analyzed by wide-angle-x-ray diffractometer (WAXD), transmission electron microscope (TEM), thermo gravimetric analyzer (TGA), differential scanning calorimeter (DSC), dynamic mechanical analyzer (DMA) and scanning electron microscope (SEM). TEM studies have shown a better dispersion of nanoparticles in case of ethylene-octene copolymer-epoxy resin-functionalized-nanosilica nanocomposite (mPE-ENS) than that of ethylene-octene copolymer-nanosilica nanocomposite (mPE-NS). The tensile tests show that organic modification of nanosilica particles brings up an appreciable increase in yield strength, ultimate tensile strength and elongation at break of the polymer. DMA studies have shown an increase in the storage modulus and glass transition temperature for mPE-ENS with respect to mPE-NS. Further, the TGA results have shown a higher thermal stability for mPE-ENS in comparison to mPE-NS.     

New Addition Reactions of Organometal Compounds with 4,4-Dimethyl-1,3-thiazole-5(4H)-thiones

Addition reactions of organometallic reagents with 4,4-disubstituted 1,3-thiazole-5(4H)-thiones were studied. Whereas the reactions with alkyllithium and alkyl Grignard reagents occurred in the thiophilic manner, the carbophilic addition was observed with allyllithium and allyl Grignard reagents. A radical reaction mechanism is proposed for rationalizing these observations (Scheme 5). A radical cyclization of the prepared 5-allyl-4,5-dihydro-1,3-thiazole-5-thiol derivatives yielded 1,6-dithia-3-azaspiro[4.4]non-2-enes (Table 4).     

Grignard-Addition an Pyridin-N-oxid

Addition of phenyl-, alkyl-, alkenyl- and alkinyl-Grignard reagents to pyridine-N-oxide in THF leads to 5-substituted (2Z, 4E)-pentadien-aldoximes 6 having (E) (syn)-configuration of the C, N-double bond. The unsaturated oximes are shown to arise through an electrocyclic ring opening reaction from the primary Grignard adducts 5 . These can be trapped by protonation at low temperature.     

Chelate-Controlled Asymmetric Synthesis of 2-Substituted 2,3-Dihydropyridin-4(1H)-ones: Synthesis of D- and L-aminodeoxyaltrose derivatives

Asymmetric methylation and phenylation of the chiral pyridinium salt 7 , as well as methylation of chiral pyridinium salt 18 , with Grignard reagents occurred in good yield and with good-to-excellent diastereoselectivities (Schemes 2 and 3, resp.). These results are best explained by assuming chelate control to govern the asymmetric alkylation/arylation process. The minimum-energy conformations of the out-of-plane twisted pyridinium salts 7 and 18 , as determined by the ‘Molecular Simulations Cerius-Dreiding II’ program, are in good agreement with the postulated asymmetric chelate-control mechanism.     

Asymmetric Induction on Copper(I) Chloride catalyzed 1,4-addition of alkylmagnesium chlorides to α, β-disubstituted (E)-enoylsultams and subsequent protonation

Successive treatment of conjugated N-enoylsultams 2 with alkyl Grignard reagents/CuCl and aq. NH₄Cl solution generated selectively two stereogenic centers at C(α) and C(β) providing, after flash chromatography and crystallization, acylsultams 5 in high purity. Mild cleavage afforded the recovered sultam auxiliary 1 and enantiomerically pure carboxylic acids 7 .     

Structure et synthèse de la damascénone (triméthyl-2,6,6-trans-crotonoyl-1-cyclohexadiène-1,3), constituant odorant de l'essence de rose bulgare (rosa damascena Mill.

Damascenone

1 DORICENONE (trade mark applied for by Firmenich & Cie, Geneva).

an odoriferous ketone isolated in minute amounts from Bulgarian rose oil (Rosa damascena Mill.) is shown to be trans-2,6,6-trimethyl-1-crotonoyl-cyclohexa-1, 3-diene (I). A synthesis starting from beta;-cyclocitral is described for this conspicuous constituent of rose oil, which displays a powerful fragrance. The synthesis of four related, more saturated ketones, damascones

2 DORINONE (trade mark applied for by Firmenich & Cie, Geneva).

, is also described.     

Synthesis and Addition Reactions of 1,3-Thiazole-5(4H)-thione Oxides

1,3-Thiazole-5(4H)-thione oxides 2 were prepared by oxidation of the corresponding 1,3-thiazole-5(4H)-thiones 1 with m-chloroperbenzoic acid (Table 1). Addition reactions of 2 with organolithium and Grignard reagents yielded 4,5-dihydro-4,4-dimethyl-1,3-thiazol-5-yl methyl sulfoxides of type 4 via thiophilic attack (Table 2). Whereas the reaction with the organolithium compounds proceeded with fair-to-excellent yields, the Grignard reagents reacted only very sluggishly. The sulfoxides 4 could also be prepared via oxidation of 4,5-dihydro-4,4-dimethyl-5-(methylthio)-1,3-thiazoles of type 3 with m-chloroperbenzoic acid, together with the corresponding sulfones 5 (Scheme 1).     

Isocamphanyl-γ-butyrolacton,ein neuer Sandelholzriechstoff

The synthesis of a new compound with a sanddalwood odour is described. The synthesis of the lactone1 has been designed by molecular considerations: a bicyclus with a side chain containing 5–7 carbon atoms and an oxygene containing osmophoric group. One route to synthesize1 leads from the ketone3 via theMannich base4 to the -ketonitrile6 which after hydrolysis to the -keto acid7 and reduction of the latter cyclises spontaneously to1. A shorter route starts from the -bromoketone13 which could be transformed by malonic ester synthesis into7. Other synthetic routes, e.g. cyanoethylation to the homologous -lactone16 aldol condensation, alkylation, carboxymethylation and carboxyethylation of3 failed as well as the preparation of the oxazoline protected 3-bromopropionic acid for aGrignard synthesis with3. 1 exhibits a sweet, warm odour, of sandalwood with an interesting note of cedarwood.

Teil der Diplomarbeit vonSchindler, K., Universität Wien, 1979.     

Technische Verfahren zur Synthese von Carotinoiden und verwandten Verbindungen aus 6-Oxo-isophoron. V. Synthese von Astacin

Technical Procedure for the synthesis of Carotenoids and Related Compounds from 6-Oxo-isophorone

1 Teil 4 dieser Reihe: [1].

. V. Synthesis of Astacene Starting from optically inactive astaxanthin intermediates, the highly oxygenated carotenoid astacene was synthesized in seven steps (55% overall yield from 6-oxo-isophorone). Key features of the new approach are base- and acid-catalyzed rearrangements of acetylenic intermediates such as those described in Schemes 2, 7 and 8.     

Angularly Substituted Octahydroindoles, Decahydroquinolines, Octahydropyrindines, and Octahydrocyclopenta[b]pyrroles by Bruylants Reaction

The easily available cycloalkanoyl acetic- and propionic acid esters are transformed to the corresponding amines by standard procedures. These in turn provided an efficient access to cyclic -aminonitriles, which were reacted with a series of Grignard reagents yielding stereoselectively the cis-configured title compounds; the scope and limitation of this route were investigated. The stereochemical assignment was achieved by X-ray crystallography and NMR spectroscopy.     

Die stereospezifische Reduktion von (1R)-3-endo-Aminocampher zu (1R)-3-endo-Aminoborneol

The highly stereospecific reduction of (1R)-3-endo-aminobornan-2-one ( 2 ) to [1R]-3-endo-amino-2-endom-bornanol ( 1 ) is described. This reaction is achieved by using alkylaluminumdichlorides, a new group of reducing agents for the reduction of the ketone 2 to the secondary alcohol 1

1 Diesc Reduktion ist Gegenstand van Patcntanmeldungen, z. B. [l].

     

Nickel-catalyzed cross-coupling of primary alkyl halides with phenylethynyl- and trimethylsilyethynyllithium reagents

A highly efficient alkyl-alkynyl coupling system is described which is promoted by a well-defined and moisture-stable pincer complex [NiCl{C₆H₃-2,6-(OPPh₂)₂}] (1). Non-activated alkyl halides could be efficiently coupled with phenylethynyl- and trimethylsilylethynyllithium reagents at room temperature. Compared to the alkylation of primary alkyl halides with alkynyllithium reagents in literatures, this method requires milder conditions (room temperature) and proceeds quickly. This research will make these readily available alkynyllithium reagents much more useful for organic synthesis.