Enantioselective Synthesis of a Polyfunctionalized Tetracycle Related to Pentacyclic Triterpenes by Using an Anionic Cycloaddition Reaction

Herein we report a convergent enantioselective synthesis of a polyfunctionalized ABCD tetracycle by using an anionic cycloaddition reaction between a chiral bicyclic CD Nazarov intermediate (see 6 ), derived from the (?)‐Weiland–Mischer ketone, and an achiral cyclohexenone (see 5 ) adequately functionalized to furnish the ring A of pentacyclic triterpenes (Scheme 5). The chiral bicyclic CD Nazarov intermediate forms ring B upon cycloaddition with the achiral cyclohexenone to yield an ABCD tetracycle with a cis‐anti‐trans‐anti‐trans configuration (see 4 ). Further transformations on this adduct allowed reduction of the angular aldehyde function at C(10) to a Me group (→ 17 ) and introduction of an unsaturation at C(5)? C(6) by using the ketone function at C(7) (→ 3 ; Scheme 6).     

Synthesis of Novel Precursors of Calicene and 7‐Methylcalicene

Cyclopent‐2‐en‐1‐one is a versatile electrophilic cyclopentadiene equivalent in reactions with 1‐bromo‐1‐lithiocyclopropanes. The synthetic sequence (outlined in Scheme 1) has been applied to the synthesis of functionalized 7‐X‐7,8‐dihydrocalicenes 13c (Scheme 3) and 13d (Scheme 4). 7‐Bromo‐7,8‐dihydrocalicene ( 13d ) is considered to be a promising precursor of the so far unknown parent calicene ( 2 ). A similar sequence has been realized for 7‐(chloromethyl)‐7,8‐dihydrocalicene ( 21a , Scheme 5) which, under appropriate conditions, could give 7‐methylcalicene ( 16 ).     

New Synthetic Approach to Naphtho[1,2‐b]furan and 4′‐Oxo‐Substituted Spiro[cyclopropane‐1,1′(4′H)‐naphthalene] Derivatives

A one‐step synthesis of ethyl 2,3‐dihydronaphtho[1,2‐b]furan‐2‐carboxylate and/or ethyl 4′‐oxospiro[cyclopropane‐1,1′(4′H)‐naphthalene]‐2′‐carboxylate derivatives 2 and 3 , respectively, from substituted naphthalen‐1‐ols and ethyl 2,3‐dibromopropanoate is described (Scheme 1). Compounds 2 were easily aromatized (Scheme 2). In the same way, 3,4‐dibromobutan‐2‐one afforded the corresponding 1‐(2,3‐dihydronaphtho[1,2‐b]furan‐2‐yl)ethanone and/or spiro derivatives 8 and 9 , respectively (Scheme 6). A mechanism for the formation of the dihydronaphtho[1,2‐b]furan ring and of the spiro compounds 3 is proposed (Schemes 3 and 4). The structures of spiro compounds 3a and 3f were established by X‐ray structural analysis. The reactivity of compound 3a was also briefly examined (Scheme 9).     

Total Synthesis of Murrayanine Involving 4,5‐Dimethyleneoxazolidin‐2‐ones and a Palladium(0)‐Catalyzed Diaryl Insertion

A new total synthesis of the natural carbazole murrayanine ( 1 ) was developed by using the 4,5‐dimethyleneoxazolidin‐2‐one 12 as starting material. The latter underwent a highly regioselective Diels–Alder cycloaddition with acrylaldehyde (=prop‐2‐enal; 13 ) to give adduct 14 (Scheme 3). Conversion of this adduct into diarylamine derivative 9 was carried out via hydrolysis and methylation (Scheme 4). Differing from our previous synthesis, in which such a diarylamine derivative was transformed into 1 by a Pd^II‐stoichiometric cyclization, this new approach comprised an improved cyclization through a more efficient Pd⁰‐catalyzed intramolecular diaryl coupling which was applied to 9 , thus obtaining the natural carbazole 1 in a higher overall yield.     

Total Synthesis of the Spermidine Alkaloid 13‐Hydroxyisocyclocelabenzine

A convergent total synthesis of 13‐hydroxyisocyclocelabenzine was developed. (3S)‐Methyl 3‐amino‐3‐phenylpropanoate ( 4 ) was used as the chiral building block. The 3,4‐dihydro‐4‐hydroxyisoquinolin‐1(2H)‐one derivative ( 5 ), the key fragment for the total synthesis, was prepared by a novel base‐catalyzed lactone‐lactam ring enlargement (Scheme 3). The resulting target C(13) epimers 3a / 3b from macrocyclization (Scheme 4) were separated by repeated flash chromatography. The absolute configuration of the synthetic alkaloid was determined by an X‐ray crystal‐structure analysis, which enabled us to determine the absolute configuration (9S,13R) for natural 3a with positive [α]_D.     

Synthesis of (±)‐Kempa‐6,8‐dien‐3‐ol (=(2aRS,3SR,4aSR,7RS,7aSR,10bSR,10cSR)‐2,2a,3,4,4a,5,6,7,7a,8,10b,10c‐Dodecahydro‐2a,7,10,10c‐tetramethylnaphth[2,18‐cde]azulen‐3‐ol)

The synthesis of kempa‐6,8‐dien‐3β‐ol ( 4a ), as a synthetic leading model of the natural product 4b , was carried out starting from intermediate 12 , the synthetic route of which has been developed previously (Scheme 1). The conversion of 12 to the model compound 4a involved the elaboration of three structure modifications by three processes, Tasks A, B, and C (see Scheme 2). Task A was achieved by epoxy‐ring opening of 41 with Me₃SiCl (Scheme 9), and Task B being performed by oxidation at the 13‐position, followed by hydrogenation, and then epimerization (Schemes 4 and 5). The removal of the 2‐OH group from 12 (Task C) was achieved via 30b according to Scheme 6, whereby 30b was formed exclusively from 30a / 31a 1 : 1 (Scheme 7). In addition, some useful reactions from the synthetic viewpoint were developed during the course of the present experiments.     

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).     

Stereoselective Total Synthesis of (11β)‐11‐Methoxycurvularin

A simple and highly efficient stereoselective total synthesis of (11β)‐11‐methoxycurvularin ( 5 ), a polyketide natural product, was achieved. The synthesis commenced with a Cu‐mediated regioselective opening of (2S)‐2‐methyloxirane ( 6 ) and comprised a Keck asymmetric allylation and intramolecular Friedel–Crafts acylation as key steps (Scheme 2).     

Efficient Synthesis of (−)‐(R)‐Muscone by Enantioselective Protonation

A new synthesis of (?)‐(R)‐muscone ((R)‐ 1 ) by means of enantioselective protonation of a bicyclic ketone enolate as the key step (see 6 →(S)‐ 4 in Scheme 2) is presented. The C₁₅ macrocyclic system is obtained by ozonolysis (Scheme 7).     

A Facile and Efficient Synthesis of Arylsulfonamido‐Substituted 1,5‐Benzodiazepines and N‐[2‐(3‐Benzoylthioureido)aryl]‐3‐oxobutanamide Derivatives

A facile and efficient synthesis of 1,5‐benzodiazepines with an arylsulfonamido substituent at C(3) is described. 1,5‐Benzodiazepine, derived from the condensation of benzene‐1,2‐diamine and diketene, reacts with an arylsulfonyl isocyanate via an enamine intermediate to produce the title compounds of potential synthetic and pharmacological interest in good yields (Scheme 1). In addition, reaction of benzene‐1,2‐diamine and diketene in the presence of benzoyl isothiocyanate leads to N‐[2‐(3‐benzoylthioureido)aryl]‐3‐oxobutanamide derivatives (Scheme 2). This reaction proceeds via an imine intermediate and ring opening of diazepine. The structures were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses. A plausible mechanism for this type of cyclization is proposed (Scheme 3).     

Chromium‐Mediated Dearomatization: Application to the Synthesis of Racemic 15‐Acetoxytubipofuran and Asymmetric Synthesis of Both Enantiomers

An efficient dearomatization process of [Cr(arene)(CO)₃] complexes initiated by a nucleophilic acetaldehyde equivalent is detailed. It generates in a one‐pot reaction three C? C bonds and two stereogenic centers. This process allowed a rapid assembly of a cis‐decalin ring system incorporating a homoannular diene unit in just two steps starting from aromatic precursors (Scheme 2). The method was applied to the total synthesis of the eudesmane‐type marine furanosesquiterpene (±)‐15‐acetoxytubipofuran ( 2 ). Two routes were successfully used to synthesize the γ‐lactone precursor of the furan ring. The key step in the first approach was a Pd‐catalyzed allylic substitution (Scheme 3), while in the second approach, an Eschenmoser–Claisen rearrangement was highly successful (Scheme 4). The Pd‐catalyzed allylic substitution could be directed to give either the (normal) product with overall retention as major diastereoisomer or the unusual product with inversion of configuration (see Table). For the synthesis of the (?)‐enantiomer (R,R)‐ 2 of 15‐acetoxytubipofuran, an enantioselective dearomatization in the presence of a chiral diether ligand was implemented (Scheme 7), while the (+)‐enantiomer (S,S)‐ 2 was obtained via a diastereoselective dearomatization of an arene‐bound chiral imine auxiliary (Scheme 8). Chiroptical data suggest that a revision of the previously assigned absolute configuration of the natural product is required.     

Synthesis of Derivatives of the Optically Active β‐Amino Acids from (+)‐Car‐2‐ene

The reaction of (+)‐car‐2‐ene ( 4 ) with chlorosulfonyl isocyanate (=sulfuryl chloride isocyanate; ClSO₂NCO) led to the tricyclic lactams 6 and 8 corresponding to the initial formation both of the tertiary carbenium and α‐cyclopropylcarbenium ions (Scheme 2). A number of optically active derivatives of β‐amino acids which are promising compounds for further use in asymmetric synthesis were synthesized from the lactams (see 16, 17 , and 19 – 21 in Scheme 3).     

Formal Synthesis of (−)‐Cephalotaxine

A formal synthesis of (?)‐cephalotaxine ( 1 ) by means of a highly stereoselective radical carboazidation process is reported. The synthesis begins with the protected (S)‐cyclopent‐2‐en‐1‐ol derivative 10 and uses the concept of self‐reproduction of a stereogenic center (Schemes 5 and 6). For this purpose, the double bond adjacent to the initial chiral center in 10 is converted into an acetonide after stereoselective dihydroxylation. The initial alcohol function is used to build an exocyclic methylene group suitable for the carboazidation process 8 → 7 (Scheme 7). Finally the protected diol moiety is converted back to an alkene ( 14 → 15 → 6 ) and used for the formation of ring B via a Heck reaction ( 6 →(?)‐ 16 ; Scheme 8).     

Insulated Molecular Wires: Dendritic Encapsulation of Poly(triacetylene) Oligomers,Attempted Dendritic Stabilization of Novel Poly(pentaacetylene) Oligomers,and an Organometallic Approach to Dendritic Rods

Multinanometer‐long end‐capped poly(triacetylene) (PTA) and poly(pentaacetylene) (PPA) oligomers with dendritic side chains were synthesized as insulated molecular wires. PTA Oligomers with laterally appended Fréchet‐type dendrons of first to third generation were prepared by attaching the dendrons ( 8 , 13 , and 17 , respectively, Scheme 1) to (E)‐enediyne 18 by a Mitsunobu reaction and subsequent Glaser‐Hay oligomerization under end‐capping conditions (Scheme 2). Whereas first‐generation oligomers up to the pentamer were isolated ( 1a – e ), for reasons of steric overcrowding, only oligomers up to the trimer ( 2a – c ) were formed at the second‐generation level, and only the end‐capped monomer and dimer ( 3a , b ) were isolated at the third‐generation level. By repetitive sequences of hydrosilylation (with the Karstedt catalyst), followed by allylation or vinylation, a series of carbosilane dendrons were also prepared (Schemes 3 and 4). Attachment of the second‐generation wedge 40 to (E)‐enediyne 18 , followed by deprotection and subsequent end‐capping Hay oligomerization, provided PTA oligomers 4a – d with lateral carbosilane dendrons (Scheme 5). UV/VIS Studies (Figs. 5 – 10) demonstrated that the insulating dendritic layers did not alter the electronic characteristics of the PTA backbone, even at the higher‐generation levels. Despite distortion from planarity due to the bulky dendritic wedges, no loss of π‐electron conjugation along the PTA backbone was detected. A surprising (E)→(Z) isomerization of the diethynylethene (DEE) core in the third generation derivative 3a was observed, possibly photosensitized by the bulky Fréchet‐type dendritic wedge. Electrochemical investigations by steady‐state voltammetry and cyclic voltammetry showed that the first reduction potential of the PTA oligomer with Fréchet‐type dendrons is shifted to more negative values as the dendritic coverage increases. With compounds 5a – c , the first oligomers with a poly(pentaacetylene) backbone were obtained by oxidative Hay oligomerization under end‐capping conditions (Scheme 6). The synthesis of dendritic PPA oligomers by oxidative coupling of (E)‐enetetrayne 60 under end‐capping conditions provided oligomers 61a – d , which were formed as mixtures of stereoisomers due to unexpected thermal (E)→(Z) isomerization (Scheme 8). In another novel approach towards dendritic encapsulation of molecular wires with a Pt‐bridged tetraethynylethene (TEE) oligomeric backbone, the trans‐dichloroplatinum(II) complex trans‐ 67 with dendritic phosphane ligands (Fig. 14) was coupled under Hagihara conditions to mono‐deprotected 69 under formation of the extended monomer 65 (Scheme 12). Again, an unexpected thermal (E)→(Z) isomerization, possibly induced by steric strain between TEE moieties and dendritic phosphane ligands in the unstable complex, led to the isolation of 65 as an isomeric mixture only.     

‘Click Synthesis’ of Some Novel Benzimidazol Oxime Ethers Containing Heterocycle Residues as Potential ß‐Adrenergic Blocking Agents

The ‘click synthesis’ of some novel O‐substituted oximes, 5a – 5j , which contain heterocycle residues, as new analogs of ß‐adrenoceptor antagonists is described (Scheme 1). The synthesis of these compounds was achieved in four steps. The formation of (E)‐2‐(1H‐benzo[d]imidazol‐1‐yl)‐1‐phenylethanone oxime, followed by their reaction with 2‐(chloromethyl)oxirane, afforded mixture of oil compounds 3 and 4 , which by a subsequent tetra‐n‐butylammonium bromide (TBAB)‐catalyzed reaction with N H heterocycle compounds (Scheme 1), led to the target compounds 5a – 5j in good yields.     

Tetrathiafulvalene (TTF)‐Bridged Resorcin[4]arene Cavitands: Towards New Electrochemical Molecular Switches

We report the synthesis of novel resorcin[4]arene‐based cavitands featuring two extended bridges consisting of quinoxaline‐fused TTF (tetrathiafulvalene) moieties. In the neutral form, these cavitands were expected to adopt the vase form, whereas, upon oxidation, the open kite geometry should be preferred due to Coulombic repulsion between the two TTF radical cations (Scheme 2). The key step in the preparation of these novel molecular switches was the P(OEt)₃‐mediated coupling between a macrocyclic bis(1,3‐dithiol‐2‐thione) and 2 equiv. of a suitable 1,3‐dithiol‐2‐one. Following the successful application of this strategy to the preparation of mono‐TTF‐cavitand 3 (Scheme 3), the synthesis of the bis‐TTF derivatives 2 (Scheme 4) and 19 (Scheme 5) was pursued; however, the target compounds could not be isolated due to their insolubility. Upon decorating both the octol bowl and the TTF cavity rims with long alkyl chains, the soluble bis‐TTF cavitand 23 was finally obtained, besides a minor amount of the novel cage compound 25a featuring a highly distorted TTF bridge (Scheme 6). In contrast to 25a , the deep cavitand 23 undergoes reversible vase → kite switching upon lowering the temperature from 293 to 193 K (Fig. 1). Electrochemical studies by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) provided preliminary evidence for successful vase → kite switching of 23 induced by the oxidation of the TTF cavity walls.     

Synthesis of Nonsymmetrically N,N′‐Diaryl‐Substituted 4,4′‐Bipyridinium Salts with Redox‐Tunable and Titanium Dioxide (TiO2)‐Anchoring Properties

A general method for the synthesis of so far unknown nonsymmetrically substituted N‐aryl‐N′‐aryl′‐4,4′‐bipyridinium salts is presented (Scheme 1). The common intermediate in all procedures is N‐(2,4‐dinitrophenyl)‐4,4′‐bipyridinium hexafluorophosphate ( 1 ⋅ ). For the synthesis of nonsymmetric arylviologens, 1 ⋅ was arenamine‐exchanged by the Zincke reaction, and then activated at the second bipyridine N‐atom with 2,4‐dinitrophenyl 4‐methylbenzenesulfonate. The detailed preparation of the six N‐aryl‐N′‐aryl′‐viologens 21 – 26 is discussed (Scheme 2). The generality of the procedure is further exemplified by the synthesis of two nonsymmetrically substituted N‐aryl‐N′‐benzyl‐ (see 11 and 12 ), and seven N‐aryl‐N′‐alkyl‐4,4′‐bipyridinium salts (see 28 – 34 ) including substituents with metal oxide anchoring and redox tuning properties. The need for these compounds and their usage as electrochromic materials, in dendrimer synthesis, in molecular electronics, and in tunable‐redox mediators is briefly discussed. The latter adjustable property is demonstrated by the reduction potential measured by cyclic voltammetry on selected compounds (Table).     

Synthesis and Reactions of 2‐[1‐Methyl‐1‐(pyrrolidin‐2‐yl)ethyl]‐1H‐pyrrole and Some Derivatives with Aldehydes: Chiral Structures Combining a Secondary‐Amine Group with an 1H‐Pyrrole Moiety as Excellent H‐Bond Donor

The synthesis of compound 2 and its derivatives 6 and 8 combining a pyrrolidine ring with an 1H‐pyrrole unit is described (Scheme 2). Their attempted usability as organocatalysts was not successful. Reacting these simple pyrrolidine derivatives with cinnamaldehyde led to the tricyclic products 3b, 9b , and 10b first (Scheme 1, Fig. 2). The final, major products were the pyrrolo‐indolizidine tricycles 3a, 9a , and 10a obtained via the iminium ion reacting intramolecularly with the nucleophilic β‐position of the 1H‐pyrrole moiety (cf. Scheme 1).     

Synthesis and Reactivity of π‐Electron‐Deficient (Arylsulfonyl)acetates

Different π‐electron‐deficient (arylsulfonyl)acetates 9 were synthesized (Scheme 1, Table 1), and their behavior as soft nucleophiles in the dialkylation reaction under phase‐transfer catalysis conditions was studied (Schemes 2 and 3, Tables 2 and 3). The [3,5‐bis(trifluoromethyl)phenyl]sulfonyl group was shown to be the best substituent for the stereoselective synthesis of (E)‐aconitates 18 via an alkylation hydro‐sulfonyl‐elimination integrated process under very mild phase‐transfer‐catalysis conditions (Scheme 5, Table 4). Sulfonylacetates 9h , i also underwent smooth Diels‐Alder reactions with acyclic and cyclic dienes via in situ formation of the appropriate dienophile through a Knoevenagel condensation with paraformaldehyde (Scheme 6). Reductive desulfonylation with Zn and NH₄Cl in THF was shown to be an efficient method for removal of the synthetically useful sulfonyl moiety (Scheme 7).     

Stereoselective Total Synthesis of Xestodecalactone C

A simple and highly efficient stereoselective total synthesis of xestodecalactone C ( IIb ), a polyketide natural product, was achieved (Scheme 2). The synthesis involved Keck's asymmetric allylation, a iodine‐induced electrophilic cyclization, and an intramolecular Friedel–Crafts acylation as key steps.