First Total Synthesis of Prionoid E,A Bioactive Rearranged Secoabietane Diterpene Quinone from Salvia prionitis

The first total synthesis of prionoid E ( 1 ), a rearranged secoabietane diterpene quinone isolated from Salvia prionitis, was achieved efficiently by means of Wacker oxidation (Scheme 5) and aldol condensation (Scheme 7) as the key steps in the synthetic sequence. Thus 1 was prepared in 15 steps in 3.7% yield starting on one hand from anisole (=methoxybenzene) and methylsuccinic anhydride (=dihydro‐3‐methylfuran‐2,5‐dione) via 4 (Scheme 3 and 5), and on the other hand from 2‐hydroxy‐2‐methylpropanoic acid via 5 (Scheme 6).     

Photochemical Reactions of N‐(2‐Halogenoalkanoyl) Derivatives of Anilines

The photochemical reactions of 2‐substituted N‐(2‐halogenoalkanoyl) derivatives 1 of anilines and 5 of cyclic amines are described. Under irradiation, 2‐bromo‐2‐methylpropananilides 1a – e undergo exclusively dehydrobromination to give N‐aryl‐2‐methylprop‐2‐enamides (=methacrylanilides) 3a – e (Scheme 1 and Table 1). On irradiation of N‐alkyl‐ and N‐phenyl‐substituted 2‐bromo‐2‐methylpropananilides 1f – m , cyclization products, i.e. 1,3‐dihydro‐2H‐indol‐2‐ones (=oxindoles) 2f – m and 3,4‐dihydroquinolin‐2(1H)‐ones (=dihydrocarbostyrils) 4f – m , are obtained, besides 3f – m . On the other hand, irradiation of N‐methyl‐substituted 2‐chloro‐2‐phenylacetanilides 1o – q and 2‐chloroacetanilide 1r gives oxindoles 2o – r as the sole product, but in low yields (Scheme 3 and Table 2). The photocyclization of the corresponding N‐phenyl derivatives 1s – v to oxindoles 2s – v proceeds smoothly. A plausible mechanism for the formation of the photoproducts is proposed (Scheme 4). Irradiation of N‐(2‐halogenoalkanoyl) derivatives of cyclic amines 5a – c yields the cyclization products, i.e. five‐membered lactams 6a , b , and/or dehydrohalogenation products 7a , c and their cyclization products 8a , c , depending on the ring size of the amines (Scheme 5 and Table 3).     

Further Synthetic Attempts towards Calicene

First synthetic attempts towards the so‐far‐unknown calicene (=5‐(cycloprop‐2‐en‐1‐ylidene)cyclopenta‐1,3‐diene) precursors 3‐(cyclopenta‐2,4‐dien‐1‐ylidene)tricyclo[3.2.2.2^2,4]nona‐6,8‐diene ( 4 ; Scheme 1), 1,4‐di(cyclopenta‐2,4‐dien‐1‐ylidene)cyclohexa‐2,5‐diene ( 5 ; Scheme 2), and (2‐bromocycloprop‐1‐en‐1‐yl)cyclopentadiene ( 6 ; X=Br; Scheme 5) are reported, which would represent very attractive compounds for gas‐phase pyrolysis ( 4 ), matrix photolysis ( 5 ), and low‐temperature HBr eliminations in solution ( 5 ).     

An Efficient Synthesis of 3‐(1H‐Tetrazol‐5‐yl)coumarins (=3‐(1H‐Tetrazol‐5‐yl)‐2H‐1‐benzopyran‐2‐ones) via Domino Knoevenagel Condensation,Pinner Reaction,and 1,3‐Dipolar Cycloaddition in Water

A novel straightforward synthesis of 3‐(1H‐tetrazol‐5‐yl)coumarins (=3‐(1H‐tetrazol‐5‐yl)‐2H‐1‐benzopyran‐2‐ones) 6 via domino Knoevenagel condensation, Pinner reaction, and 1,3‐dipolar cycloaddition of substituted salicylaldehydes (=2‐hydroxybenzaldehydes), malononitrile (propanedinitrile), and sodium azide in H₂O is reported (Scheme 1 and Table 2). This general protocol provides a wide variety of 3‐(1H‐tetrazol‐5‐yl)coumarins in good yields under mild reaction conditions.     

Studies for a Variable Synthesis of Colchicinoids: Construction of Ring A on a Heptalene Moiety

It is shown that heptalene‐4,5‐dicarboxylates 2 , which react with lithiated methyl sulfones mainly in a Michael fashion at C(3) (cf. Scheme 2), so that the formation of 3‐sulfonylbenzo[a]heptalene‐2,4‐diols 5 is repressed or completely suppressed, can be transformed into corresponding pseudo‐esters 15 (Scheme 4). These pseudo‐esters, on treatment with lithiated methyl sulfones, followed by addition of BuLi, furnish the 3‐sulfonylbenzo[a]heptalene‐2,4‐diols 5 in excellent‐to‐moderate yields without formation of Michael adducts or their follow‐up products (cf. Scheme 5 and 6). The reaction of the pseudo‐ester 15a with Li[¹³C]H₂SO₂Ph, followed by treatment with non‐labeled LiCH₂SO₂Ph and then BuLi, led to the exclusive formation of 3‐(phenylsulfonyl)‐[1‐¹³C]benzo[a]heptalene‐2,4‐diol 5a* (Scheme 9). This experiment demonstrates that the (phenylsulfonyl)acetyl groups at C(4) and C(5) of the heptalene core retain their individual positions in the course of the benzo[a]heptalene‐2,4‐diol formation. These findings are only compatible with an intramolecular rearrangement mechanism as depicted in Scheme 10.     

Metal‐Free 2,2,6,6‐Tetramethylpiperidin‐1‐yloxy Radical (TEMPO) Catalyzed Aerobic Oxidation of Hydroxylamines and Alkoxyamines to Oximes and Oxime Ethers

TEMPO‐Mediated oxidation of hydroxylamines (=hydroxyamines) and alkoxyamines to the corresponding oxime derivatives is reported (TEMPO=2,2,6,6‐tetramethylpiperidin‐1‐yloxy radical; Scheme 2). These environmentally benign oxidations proceed in good to excellent yields (Table 1). For alkoxyamines, oxidation to the corresponding oxime ethers can be performed by using dioxygen as a terminal oxidant in the presence of 5–10 mol‐% of TEMPO or 4‐substituted derivatives thereof as a catalyst (Scheme 3 and Table 2). Importantly, benzyl bromides can directly be transformed to oxime ethers via in situ alkoxyamine formation by a nucleophilic substitution followed by TEMPO‐mediated oxidation (Scheme 4 and Table 3).     

The Briggs‐Rauscher Reaction as a Test to Measure the Activity of Antioxidants

A new method for monitoring the relative activity of antioxidants is presented, and its advantages and limits are discussed. The method is based on the previously reported inhibitory effects of free‐radical scavengers on the oscillations of the Briggs‐Rauscher reaction. The effect consists of an immediate cessation of oscillations, an inhibition time that linearly depends on the concentration of the antioxidant added, and subsequent regeneration of oscillations. Here the effects of ten antioxidants (pyrocatechol (=benzene‐1,2‐diol), ferulic acid (=3‐(4‐hydroxy‐3‐methoxyphenyl)prop‐2‐enoic acid), caffeic acid (=3‐(3,4‐dihydroxyphenyl)prop‐2‐enoic acid), 2,6‐, 3,4‐, 2,4‐, 3,5‐, and 2,5‐dihydroxybenzoic acids, homovanillic acid (=4‐hydroxy‐3‐methoxybenzeneacetic acid), and resorcinol (=benzene‐1,3‐diol)) were studied in detail. Relative antioxidant activities of these substances with respect to resorcinol were determined in different ways on the basis of inhibition times. The limits of the calculated values of relative activity based on the Briggs‐Rauscher reaction are the same as those obtained with other analytical procedures and are discussed here. The new method is inexpensive: reagents and apparatus are commonly used in all chemical laboratories. The thermochemical behavior of the Briggs‐Rauscher reaction and the dependence of inhibition time on the temperature were also carefully investigated and taken into account. A semiquantitative mechanistic interpretation of the inhibitory effects based on a suitable kinetic model is given.     

A Direct Synthesis of Nucleoside Analogs Homologated at the 3′‐ and 5′‐Positions

A new route is presented to prepare analogs of nucleosides homologated at the 3′‐ and 5′‐positions. This route, applicable to both the D ‐ and L ‐enantiomeric forms, is suitable for the preparation of monomeric bis‐homonucleosides needed for the synthesis of oligonucleotide analogs. It begins with the known monobenzyl ether 3 of pent‐2‐yne‐1,5‐diol, which is reduced to alkenol 4 . Sharpless asymmetric epoxidation of 4 , followed by opening of the epoxide 5 with allylmagnesium bromide, gives a mixture of diols 6 and 7 . Protection of the primary alcohol as a silyl ether followed by treatment with OsO₄, NaIO₄, and mild acid in MeOH, followed by reduction, yields (2R,3R) {{[(tert‐butyl)diphenylsilyl]oxy}methyl}tetrahydro‐2‐(2‐hydroxyethyl)‐5‐methoxyfuran (=methyl 3‐{{[(tert‐butyl)diphenylsilyl]oxy}methyl}‐2,3,5‐trideoxy‐α/β‐D ‐erythro‐hexafuranoside; 10 ) (Scheme 1). Protected nucleobases are added to this skeleton with the aid of trimethylsilyl triflate (Scheme 2). The o‐toluoyl (2‐MeC₆H₄CO) and p‐anisoyl (4‐MeOC₆H₄CO) groups were used to protect the exocyclic amino group of cytosine. The bis‐homonucleoside analogs 11 and 14a are then converted to monothiol derivatives suitable for coupling (Schemes 3 and 4) to oligonucleotide analogs with bridging S‐atoms. This synthesis replaces a much longer synthesis for analogous nucleoside analogs that begins with diacetoneglucose (=1,2 : 5,6‐di‐O‐isopropylideneglucose), with the stereogenic centers in the final products derived from the Sharpless asymmetric epoxidation. The new route is useful for large‐scale synthesis of these building blocks for the synthesis of oligonucleotide analogs.     

Cascade Synthesis of Functionalized 2H‐Imidazo[5,1‐a]isoquinolinium Chlorides from Isoquinoline,Chloro­formamidines (=Carbamimidoyl Chlorides), and Isocyanides

Stable derivatives of 2H‐imidazo[5,1‐a]isoquinolinium chloride are obtained in good yields from the cascade reaction between isoquinoline, chloroformamidines (=carbamimidoyl chlorides), and isocyanides in dry MeCN (Scheme 1).     

Halogenation of Fluorinated 1,3,5‐Triketones

The behavior of linear and cyclic fluorinated 1,3,5‐triketones and their metal derivatives towards common halogenating agents was examined, and optimal reaction conditions for the straightforward synthesis of mono‐, di‐, and tetrahalogenated products were found (Schemes 1–3). An aromatization through a double HBr elimination from an α,α′‐dibrominated cyclohexanone was shown to be a promising synthetic route to 1,1′‐(2‐hydroxy‐1,3‐phenylene)bis[2,2,2‐trifluoroethanones] (= 2,6‐bis(trifluoroacetyl)phenols; Scheme 4). Additionally, the 1,3,5‐triketones prepared add readily H₂O or alcohols to produce novel bridged 2,6‐dihydroxypyran‐4‐ones (Scheme 2). The structure of the obtained compounds 6a and 7a was confirmed by X‐ray structure analysis.     

A One‐Pot Biginelli Synthesis of 6‐Unsubstituted 5‐Aroylpyrimidin‐2(1H)‐ones and 6‐Acetyl‐1,2,4‐triazin‐3(2H)‐ones

The three‐component Biginelli‐like cyclocondensation reaction of enamines 1 , urea, and aldehydes in dioxane/acetic acid efficiently afforded the corresponding 6‐unsubstituted 3,4‐dihydropyrimidin‐2(1H)‐ones 2 in good yields (Scheme 1, Table). The corresponding reaction of azaenamine (=hydrazone) 7 with benzaldehyde and urea afforded 6‐acetyl‐1,2,4‐triazin‐3(2H)‐ones in good yields (Scheme 3).     

Ultrasound‐Promoted Catalyst‐Free Synthesis of 2,2′‐(1,4‐Phenylene)bis[1‐acetyl‐1,2‐dihydro‐4H‐3,1‐benzoxazin‐4‐one] Derivatives

A convenient approach to 2,2′‐(1,4‐phenylene)bis[1‐acetyl‐1,2‐dihydro‐4H‐3,1‐benzoxazin‐4‐one] derivatives 4 was explored employing the one‐pot condensation of anthranilic acids (=2‐aminobenzoic acids) 1 with terephthalaldehyde (=benzene‐1,4‐dicarboxaldehyde; 2 ) under ultrasound‐irradiation conditions (Scheme 1). The reactions proceeded smoothly in the presence of excess Ac₂O in the absence of any other catalyst and solvent to afford the respective products in high yields.     

Itosides A – I,New Phenolic Glycosides from Itoa orientalis

Eight new benzoylated gentisyl alcohol (=2‐(hydroxymethyl)benzene‐1,4‐diol) glucosides, itosides A–H ( 1 – 8 ), together with the new pyrocatechol (=benzene‐1,2‐diol) glycoside itoside I ( 9 ) were isolated from the bark and twigs of Itoa orientalis (Flacourtiaceae). In itosides B–D ( 2 – 4 ), the gentisyl alcohol moiety was esterified by 1‐hydroxy‐6‐oxocyclohex‐2‐ene‐1‐carboxylic acid, while itosides E–H ( 5 – 8 ) contained instead an additional 2‐hydroxybenzoic acid moiety. The compounds were accompanied by the known derivatives 4‐hydroxytremulacin ( 10 ), poliothyrsoside ( 11 ), poliothyrsin ( 12 ), homaloside D ( 13 ), tremulacin, and pyrocatechol β‐D ‐glucopyranoside. The structures of the new compounds were elucidated by spectral and chemical methods.     

Regio‐ and Stereocontrolled Synthesis of (2R*,3R*,4R*)‐3,4‐Dichloro‐1,2,3,4,5,8‐hexahydronaphthalen‐2‐yl Acetate via Tandem SN2′ Reactions

The hydroperoxy endoperoxide 3 , obtained by photooxygenation of isotetralin (= 1,4,5,8‐tetrahydronaphthalene; 1 ), was reduced with thiourea, and the resulting intermediate 4 was converted, after acetylation with acetyl chloride, to the interesting, double‐chlorinated acetate 5 in an unprecedented tandem reaction (Scheme 1). The structures and relative configurations of 3 and 5 were determined by NMR spectroscopy and by single‐crystal X‐ray‐diffraction analyses (Figs. 1 and 2, resp.). A mechanistic rationalization for the conversion of 4 to 5 is proposed (Scheme 2).     

Synthesis of Bis‐Heterocyclic 1H‐Imidazole 3‐Oxides from 3‐Oxido‐1H‐imidazole‐4‐carbohydrazides

The reaction of 1H‐imidazole‐4‐carbohydrazides 1 , which are conveniently accessible by treatment of the corresponding esters with NH₂NH₂?H₂O, with isothiocyanates in refluxing EtOH led to thiosemicarbazides (=hydrazinecarbothioamides) 4 in high yields (Scheme 2). Whereas 4 in boiling aqueous NaOH yielded 2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thiones 5 , the reaction in concentrated H₂SO₄ at room temperature gave 1,3,4‐thiadiazol‐2‐amines 6 . Similarly, the reaction of 1 with butyl isocyanate led to semicarbazides 7 , which, under basic conditions, undergo cyclization to give 2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐ones 8 (Scheme 3). Treatment of 1 with Ac₂O yielded the diacylhydrazine derivatives 9 exclusively, and the alternative isomerization of 1 to imidazol‐2‐ones was not observed (Scheme 4). It is important to note that, in all these transformations, the imidazole N‐oxide residue is retained. Furthermore, it was shown that imidazole N‐oxides bearing a 1,2,4‐triazole‐3‐thione or 1,3,4‐thiadiazol‐2‐amine moiety undergo the S‐transfer reaction to give bis‐heterocyclic 1H‐imidazole‐2‐thiones 11 by treatment with 2,2,4,4‐tetramethylcyclobutane‐1,3‐dithione (Scheme 5).     

Facile One‐Pot Synthesis of Monosubstituted 1‐Aryl‐1H‐1,2,3‐triazoles from Arylboronic Acids and Prop‐2‐ynoic Acid (=Propiolic Acid) or Calcium Acetylide (=Calcium Carbide) as Acetylene Source

The synthesis of monosubstituted 1‐aryl‐1H‐1,2,3‐triazoles was achieved in a one‐pot reaction from arylboronic acids and prop‐2‐ynoic acid or calcium acetylide (=calcium carbide), respectively, as a source of acetylene, with yields ranging from moderate to excellent (Scheme 1, Table 2). The reaction conditions were successfully applied to arylboronic acids, including analogs with various functionalities. Unexpectedly, the 1,2,3‐triazole moiety promoted a regioselective hydrodebromination (Scheme 2).     

An Improved Preparation of D‐Glyceraldehyde 3‐Phosphate and Its Use in the Synthesis of 1‐Deoxy‐D‐xylulose 5‐Phosphate

D ‐Glyceraldehyde 3‐phosphate (=D ‐GAP; 2 ) was prepared by an improved chemical method (Scheme 2), and it was then employed to synthesize 1‐deoxy‐D ‐xylulose 5‐phosphate (=DXP; 3 ) which is enzymatically one of the key intermediates in the MEP ( 4 ) terpenoid biosynthetic pathway (Scheme 1). The recombinant DXP synthase of Rhodobacter capsulatus was used to catalyze the condensation of D ‐glyceraldehyde 3‐phosphate ( 2 ) and pyruvate (=2‐oxopropanoate; 1 ) to produce the sugar phosphate 3 (Scheme 2). The simple two‐step chemoenzymatic route described affords DXP ( 3 ) with more than 70% overall yield and higher than 95% purity. The procedure may also be used for the synthesis of isotope‐labeled DXP ( 3 ) by using isotope‐labeled pyruvate.     

An Approach to the Synthesis of 7‐Amino‐6‐imino‐9‐phenyl‐6H‐benzo[c]chromene‐8‐carbonitrile Derivatives via a Three‐Component Reaction under Ultrasonic Irradiation

An efficient synthesis of 7‐amino‐6‐imino‐9‐phenyl‐6H‐benzo[c]chromene‐8‐carbonitrile derivatives 3 by a three‐component reaction of salicylaldehydes (=2‐hydroxybenzaldehydes) 1 , malononitrile (=propanedinitrile), and 2‐(1‐arylethylidene)malononitrile 2 under ultrasonic irradiation in EtOH is reported. Good yields, short reaction times, and easy purification are the main advantages of the present method. The structures were confirmed spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses. A plausible mechanism for this reaction is proposed (Scheme 2).     

Thionation of ω‐Acylamino Ketones with Lawesson's Reagent: Convenient Synthesis of 1,3‐Thiazoles and 4H‐1,3‐Thiazines

The reaction of ω‐acylamino ketones with Lawesson's reagent (=2,4‐bis(4‐methoxyphenyl)‐1,3,2,4‐dithiadiphosphetane 2,4‐disulfide; LR ) is described. Treatment of 2‐acylamino ketones 1 (n=0) with LR gave 1,3‐thiazole derivatives 3 in good yields (Scheme 1 and Table 1). The 4H‐1,3‐thiazines 4 were obtained as main products by treatment of 3‐acylamino ketones 2 (n=1) with an equimolar amount of LR , while mainly the corresponding 3‐(thioacyl)amino ketones 5 were isolated when 0.5 equiv. of LR was used. The 3‐acylamino esters 7 also reacted with LR to give the corresponding 3‐(thioacyl)amino esters 8 (Scheme 3 and Table 2).     

Stereoconvergent Generation of a Contrasteric syn‐Bicyclopropylidene (=syn‐Cyclopropylidenecyclopropane) by Stille‐Like Coupling

Stereoisomerically pure endo‐ and exo‐7‐halo‐7‐(trimethylstannyl)benzonorcar‐3‐enes (=endo‐ and exo‐(1‐halo‐1a,2,7,7a‐tetrahydro‐1H‐cyclopropa[b]naphthalen‐1‐yl)trimethylstannane) 4 and 6 were selectively obtained by lithium? tin or magnesium? tin transmetalation in good yields (Scheme 2 and 3). The reaction of these compounds with copper(I) thiophene‐2‐carboxylate (CuTC) produced in both cases the corresponding C_S‐symmetric bicyclopropylidene (=cyclopropylidenecyclopropane) syn‐ 1 , a single diastereoisomer (Schemes 5 and 6). The structure of syn‐ 1 was undoubtedly elucidated by X‐ray single crystal diffraction. The coupling mechanism of the carbenoid cyclopropane is discussed (Scheme 7).