‘Click Synthesis’ of Some Novel O‐Substituted Oximes Containing 1,2,3‐Triazole‐1,4‐diyl Residues as New Analogs of β‐Adrenoceptor Antagonists

The ‘click synthesis’ of some novel O‐substituted oximes, 7a – 7t , which contain 1,2,3‐triazolediyl residues, as new analogs of β‐adrenoceptor antagonists is described (Schemes 1–4). The synthesis of these compounds was achieved in four to five steps. The formation of oximes of 9H‐fluoren‐9‐one and benzophenone, i.e., 9a and 9b , respectively, followed by their reaction with propargyl bromide, afforded O‐propargyl oximes 10a and 10b , respectively, which by a subsequent CuI‐catalyzed Huisgen cycloaddition with prepared β‐azido alcohols 11a – 11j (Schemes 2 and 3), led to the target compounds 7a – 7t in good yields.     

A Novel Access to Ionone-Type Compounds: (E)-4-oxo-β-ionone and (E)Oxo-β-irone via metal-catalyzed intramolecular reactions of α-diazo ketones with furans

(E)-5-Demethyl-4-oxo-β-ionone ( 2 ), (E)-4-oxo-β-ionone ( 3 ), (E)-4-oxo-β-irone ( 4 ), and the five-membered ring analogs 36 – 41 were synthesized by a novel, convergent route starting from 2-methylfuran ( 1 ). A recently discovered, intramolecular reaction of 2-(diazoacyl)furans, catalyzed by dirhodium tetraacetate, leading to dienediones served as key step, thereby testing its utility in natural-product synthesis for the first time.     

A Novel Asymmetric Synthesis of 3‐(1H‐Pyrrol‐1‐yl)‐Substituted β‐Lactams via a Bismuth Nitrate‐Catalyzed Reaction

The reaction of racemic α‐keto β‐lactams 5a – 5c with the commercially available chiral compound trans‐4‐hydroxy‐L ‐proline ( 6 ) in the presence of a catalytic amount of Bi(NO₃)₃?5 H₂O in EtOH gave a diastereoisomer mixture of β‐lactams with a pyrrole ring at C(3) ( 7 to 12 ). This is the first enantioselective synthesis of optically active β‐lactams (=azetidin‐2‐ones) that possess a pyrrolyl residue at C(3), in a single step.     

Nucleotides,Part LXVI , β‐Heteroarylethyl Groups – New Phosphate‐Protecting Groups for Phosphotriester Chemistry

The β‐heteroaryl‐substituted ethanols 6 – 10 were synthesized and, together with pyridine‐2‐ethanols and pyridine‐4‐ethanols, were tested as a new type of phosphate‐protecting groups in the synthesis of oligonucleotides by the phosphotriester approach. The synthesis of 5′‐O‐(monomethoxytrityl)thymidine 3′‐(β‐heteroarylethyl 2,5‐dichlorophenyl phosphates) 13 – 17 and 21 provided useful monomeric building blocks in which the various blocking groups could be removed selectively by acid (MeOTr), oximate (2,5‐dichlorophenyl phosphate), and 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) (heteroarylethyl phosphate) treatment. The new, fully blocked dimers 38 – 41 , with β‐heteroarylethyl protecting groups in the phosphate moiety, were synthesized. The β‐heteroarylethyl groups show a broad range of stability towards base treatment in aprotic solvents depending upon the activation of the H−C(β) atoms by the heterocyclic moiety.     

Automated Solid‐Phase Synthesis and Structural Investigation of β‐Peptidosulfonamides and β‐Peptidosulfonamide/β‐Peptide Hybrids: β‐Peptidosulfonamide and β‐Peptide Foldamers are Two of a Different Kind

Fmoc‐protected β‐aminoethane sulfonylchlorides can be employed for efficient automated solid phase synthesis of β‐peptidosulfonamides and β‐peptidosulfonamide/β‐peptide hybrids containing one or more β‐peptidosulfonamide residues. Thus, Fmoc‐protected β‐aminoethane sulfonylchlorides 5a – c led to the hexa‐β‐peptidosulfonamide 9 and the nona‐β‐peptidosulfonamide 10 . In addition, the β‐peptidosulfonamide/β‐peptide hybrids 13 and 16 , consisting of six and nine β‐residues, respectively, and containing a single β‐peptidosulfonamide unit in the middle, as well as the peptidosulfonamide/β‐peptide hybrid 15 with nine β‐residues, including an N‐terminal β‐peptidosulfonamide residue, were synthesized by automated solid‐phase synthesis. Both CD and NMR spectroscopic measurements did not indicate any helical secondary structure for 9 and 10 . As was shown by CD‐measurements, the β‐peptidosulfonamide residue in the hybrids 13, 15 , and 16 acts as a ‘helix breaker', especially when located in the middle of the hybrid chain ( 13 and 16 ), but, although to a lesser extent, also at the N‐terminus.     

Reactions of Complex Ligands. Part 107 Densely Substituted Hydroquinoid Phenanthrene and Triphenylene Cr(CO)3 Complexes: Chromium‐Templated Synthesis and Molecular Structure

Densely substituted hydroquinoid phenanthrene ( 10 – 18 ), acephenanthrene ( 19 ), and triphenylene chromium tricarbonyl complexes ( 20 – 22 ) have been prepared via benzannulation of naphthalenyl ( 1 – 7 ), acenaphthenyl ( 8 ) and phenanthrenyl carbene complexes ( 9 ), respectively. The naphthalenyl, acenaphthenyl and phenanthrenyl carbene complexes 1 – 9 were obtained in 52–88 % yield starting from commercially available bromoarenes by dehalolithiation, addition of hexacarbonyl chromium to the lithioarene and O‐alkylation of the resulting acyl chromates with trimethyloxonium tetrafluoroborate (Fischer route). The benzannulation of the aryl carbene complexes (either with 3‐hexyne / (t‐butyl)dimethylsilyl chloride or with (t‐butyl)dimethylsilylethyne) allowed the regiospecific synthesis of the oligocyclic hydroquinoid arene tricarbonyl chromium complexes 10 – 22 in 44–94 % yield thus providing a two‐step synthesis with overall yields of 18 ‐ 80 %. Under the kinetic reaction conditions used the metal atom is exclusively coordinated to the persubstituted terminal hydroquinoid ring. The molecular structures of phenanthrene complexes 10 , 12 – 14 , and 16 , acephenanthrene complex 19 , and triphenylene complexes 20 and 21 in the solid state have been determined by X‐ray crystallography. The carbonyl ligands either adopt an eclipsed ( 10 , 12 , 14 , 16 , 19 , 20 ) or staggered ( 13 , 21 ) exo‐conformation pointing away from the center of the phenanthrene, acephenanthrene and triphenylene ligands, respectively. The coordination of the metal atom to the hydroquinoid ring is unsymmetric with the largest metal‐carbon distances found between the chromium atom and one bridgehead carbon and the ring carbon atom bearing the bulky (t‐butyl)dimethylsilyloxy (TBDMSO) substituent.     

Five New β‐Carboline‐Type Alkaloids from Stellaria dichotoma var. lanceolata

Five new β‐carboline‐type alkaloids, dichotomines F–J ( 1 – 5 , resp.), along with nine known compounds, dichotomides I, III, V, and VII ( 6 – 9 , resp.), stellarines A and C ( 10 – 11 , resp.), dichotomine B ( 12 ), glucodichotomine B ( 13 ), and 1‐acetyl‐3‐carboxy‐β‐carboline ( 14 ), were isolated from the roots of Chinese medicinal plant Stellaria dichotoma L. var. lanceolata. Their structures were determined by chemical and spectroscopic means. Compounds 12 and 13 exhibited moderate cytotoxicity.     

A New ent‐Kaurane Diterpene from Stems of Alibertia macrophylla K. Schum. (Rubiaceae)

Phytochemical investigations of the stems of a specimen of Alibertia macrophylla led to the isolation and characterization of the new diterpene ent‐kaurane‐2β,3α,16α‐triol ( 1 ), along with triterpenes 2 – 8 , iridoids 9 – 12 , and phenolic acids 13 – 15 . The structure of 1 was established based on spectroscopic studies (¹H‐ and ¹³C‐NMR, IR, and HR‐ESI‐MS). This is the first report of the isolation of a diterpene from the Alibertia genus in Rubiaceae.     

β-Cleavage of Bis(homoallylic) Potassium Alkoxides. Preparation of 3-Hydroxypropyl and 4-Hydroxybutyl Propenyl Ketones from γ- and δ-Lactones. Synthesis of (±)-Rose oxide

Starting from γ- and δ-lactones 1 – 3 , a two-step preparation of 3-hydroxypropyl and 4- hydroxybutyl propenyl ketones 10 – 18 is described, involving as the key step the β-cleavage of the bis(homoallylic) potassium alkoxides 4a – 9a . The novel methodology is illustrated by a short synthesis of (±)-rose oxide( 20 ).     

Synthesis of β3‐Peptides and Mixed α/β3‐Peptides by Thioligation

Five β‐peptide thioesters ( 1 – 5 , containing 3, 4, 10 residues) were prepared by manual solid‐phase synthesis and purified by reverse‐phase preparative HPLC. A β‐undecapeptide ( 6 ) and an α‐undecapeptide ( 7 ) with N‐terminal β³‐HCys and Cys residues were prepared by manual and machine synthesis, respectively. Coupling of the thioesters with the cysteine derivatives in the presence of PhSH (Scheme and Fig. 1) in aqueous solution occurred smoothly and quantitatively. Pentadeca‐ and heneicosapeptides ( 8 – 10 ) were isolated, after preparative RP‐HPLC purification, in yields of up to 60%. Thus, the so‐called native chemical ligation works well with β‐peptides, producing larger β³‐ and α/β³‐mixed peptides. Compounds 1 – 10 were characterized by high‐resolution mass spectrometry (HR‐MS) and by CD spectroscopy, including temperature and concentration dependence. β‐Peptide 9 with 21 residues shows an intense negative Cotton effect near 210 nm but no zero‐crossing above 190 nm, (Figs. 2–4), which is characteristic of β‐peptidic 3₁₄‐helical structures. Comparison of the CD spectra of the mixed α/β‐pentadecapeptide ( 10 ) and a helical α‐peptide (Fig. 5) indicate the presence of an α‐peptidic 3.6₁₃ helix.     

Preparation of β2‐Amino Acid Derivatives (β2hThr, β2hTrp, β2hMet, β2hPro, β2hLys,Pyrrolidine‐3‐carboxylic Acid) by Using DIOZ as Chiral Auxiliary

The title compounds were prepared from valine‐derived N‐acylated oxazolidin‐2‐ones, 1 – 3, 7, 9 , by highly diastereoselective (≥ 90%) Mannich reaction (→ 4 – 6 ; Scheme 1) or aldol addition (→ 8 and 10 ; Scheme 2) of the corresponding Ti‐ or B‐enolates as the key step. The superiority of the ‘5,5‐diphenyl‐4‐isopropyl‐1,3‐oxazolidin‐2‐one’ (DIOZ) was demonstrated, once more, in these reactions and in subsequent transformations leading to various t‐Bu‐, Boc‐, Fmoc‐, and Cbz‐protected β²‐homoamino acid derivatives 11 – 23 (Schemes 3–6). The use of ω‐bromo‐acyl‐oxazolidinones 1 – 3 as starting materials turned out to open access to a variety of enantiomerically pure trifunctional and cyclic carboxylic‐acid derivatives.     

Amino‐Claisen Rearrangements and Diels‐Alder Reactions of Ketene N,O‐Acetals: Reactivity Studies. On the Way to a Novel Tandem Process?

We report the synthesis of N‐benzyl‐N‐[(E)‐buta‐1,3‐dienyl]propanamide ( 6 ) and its corresponding O‐silyl‐substituted ketene N,O‐acetal 7 and their Diels‐Alder reaction. Propanamide 6 reacted smoothly, whereas the yield obtained from 7 was low, probably due to polymerization of the dienophile induced by electron transfer. The ketene N,O‐acetals 27a – g were synthesized starting from the corresponding benzamides 25a – e (Scheme 9). The ketene N,O‐acetals 27a – g showed increased stabilities and underwent amino‐Claisen rearrangements under thermal conditions. Using catalysts, interesting side reactions leading either to the annulated systems rac‐ 35 – 37 or to a β‐lactam rac‐ 34 were observed.     

Der zweistufige Carbanion-Mechanismus der Fragmentierung von 3-Aminopropylbenzoaten. Fragmentierungs-Reaktionen. 25. Mitteilung

The unsubstituted and p-substituted benzoates 2b – 2e of 3-dimethylamino-2,2bis(p-nitrophenyl)-propanol ( 2a ) undergo quantitative fragmentation in 80% ethanol yielding 1,1-bis(p-nitrophenyl)-ethylene ( 5 ) besides formaldehyde and dimethylamine, the hydrolysis products of the imonium ion 3 . The corresponding alcohol 2a , however, yields 2,2-bis(p-nitrophenyl)-ethanol ( 9 ) in addition to fragmentation products. Conversely, no fragmentation is observed with the benzoates 6b – 6e of 3-dimethylamino-2,2-diphenylpropanol ( 6a ) which lack electronwithdrawing substituents in the β-phenyl groups. These results are in agreement with a two-step carbanion mechanism (Scheme 2) involving the ionization of the aminoalkohol 2a and its esters 2b – 2e to the imonium ion 3 and the carbanions 4a – 4e . The latter undergo competitive cleavage, recombination and protonation to 5 , 2 and 9 , respectively, depending on the nucleofugal activity of –X. These conclusions are supported by the first-order rate constants for the benzoates 2b – 2e which differ merely by a factor of three. Since the p-substituents in the benzoate groups have only a minor effect on the reaction rate the bonds to the nucleofugal groups are not appreciably broken in the rate determining step.     

Nine New Sesquiterpenes from Dendrobium nobile

Nine new sesquiterpenes, i.e., dendronobilins A–I ( 1 – 9 ), with copacamphane‐type ( 1 ), picrotoxane‐type ( 2 – 6 ), muurolene‐type ( 7 ), alloaromadendrane‐type ( 8 ), and cyclocopacamphane‐type ( 9 ) skeletons, were isolated from the 60% EtOH extract of the stems of Dendrobium nobile. Their structures were established as (1R,2R,4S,5S,6S,8S,9R)‐2,8‐dihydroxycopacamphan‐15‐one ( 1 ), (2β,3β,4β,5β)‐2,4,11‐trihydroxypicrotoxano‐3(15)‐lactone ( 2 ), (2β,3β,5β,9α,11β)‐2,11‐epoxy‐9,11,13‐trihydroxypicrotoxano‐3(15)‐lactone ( 3 ), (2β,3β,5β,12R*)‐2,11,13‐trihydroxypicrotoxano‐3(15)‐lactone ( 4 ), (2β,3β,5β,12S*)‐2,11,13‐trihydroxypicrotoxano‐3(15)‐lactone ( 5 ), (2β,3β,5β,9α)‐9,10‐cyclo‐2,11,13‐trihydroxypicrotoxano‐3(15)‐lactone ( 6 ), (9β,10α)‐muurol‐4‐ene‐9,10,11‐triol ( 7 ), (10α)‐alloaromadendrane‐10,12,14‐triol ( 8 ), and (5β)‐cyclocopacamphane‐5,12,15‐triol ( 9 ) on the basis of spectroscopic analysis. The absolute configuration of compound 1 was tentatively assigned as (1R,2R,4S,5S,6S,8S,9R) according to its CD spectrum and the octant rule. Compounds 1 and 4 – 9 were inactive in our preliminary in vitro immunomodulatory bioassay.     

Eight New Cucurbitane Glycosides,Kuguaglycosides A – H,from the Root of Momordica charantia L.

Eight new cucurbitane glycosides, kuguaglycosides A–H ( 1 – 8 , resp.), together with five known analogues, 3β,23‐dihydroxycucurbita‐5,24‐dien‐7β‐yl β‐D ‐glucopyranoside ( 9 ), karaviloside III ( 10 ), karaviloside V ( 11 ), karaviloside XI ( 12 ), and momordicoside K ( 13 ), were isolated from the root of Momordica charantia L. The structures of the new compounds were determined on the basis of spectroscopic and chemical methods.     

Palmitoleate (=(9Z)‐Hexadeca‐9‐enoate) Esters of Oleanane Triterpenoids from the Golden Flowers of Tagetes erecta: Isolation and Autoxidation Products

Six oleanane‐type triterpenoid esters were isolated from the golden flowers of Tagetes erecta. Spectral studies characterized their structures as 3‐O‐[(9Z)‐hexadec‐9‐enoyl]erythrodiol ( 1 ), 11α,12α:13β,28‐diepoxyoleanan‐3β‐yl (9Z)‐hexadec‐9‐enoate ( 2 ), 13β,28‐epoxyolean‐11‐en‐3β‐yl (9Z)‐hexadec‐9‐enoate ( 3 ), 28‐hydroxy‐11‐oxoolean‐12‐en‐3β‐yl (9Z)‐hexadec‐9‐enoate ( 4 ), 3‐O‐[(9Z‐hexadec‐9‐enoyl]‐β‐amyrin ( 5 ), and 11‐oxoolean‐12‐en‐3β‐yl (9Z)‐hexadec‐9‐enoate ( 6 ). Compounds 1 – 4 and 6 are new natural products, while the known 5 was isolated for the first time from the genus Tagetes, from which only one triterpenoid has earlier been obtained. Aerial oxidation (autoxidation) converted amyrin 1 into 2 – 4 and transformed amyrin 5 into 6 . The configuration of 1 – 6 and an autoxidation mechanism (Scheme) involving the formation of the intermediate 11α‐hydroxyolean‐12‐ene derivatives 1b and 5b on thermal decomposition of the labile 11α‐OOH derivatives 1a and 5a , respectively, under neutral conditions are discussed. For the first time, the reactivity of the allylic H? C(11) bond of triterpenoids of type 1 and 5 toward aerial oxidation was observed. The long‐chain ester group at C(3) of 1 and 5 may be responsible for their labile nature, as β‐amyrin ( 7 ), erythrodiol ( 8 ), and ursolic acid were found to be inert toward autoxidation.     

Two New Polyhydroxylated Steroids from the Hainan Soft Coral Sinularia sp.

Two new polyhydroxylated steroids, (2β,3β,4α,5α,8β,11β)‐4‐methylergost‐24(28)‐ene‐2,3,8,11‐tetrol‐( 1 ) and (3β,5α,6β)‐ergosta‐22,24(28)‐diene‐3,5,6,19‐tetrol ( 3 ), together with the six known related steroids 2 and 4 – 8 , were isolated from the Hainan soft coral Sinularia sp. Their structures were elucidated on the basis of spectroscopic analysis and by comparison with previously reported data. The structure of the known compound 9 (hyrtiosterol) was revised as 2 by extensive analysis of the ROESY data and by the NOE difference experiment.     

β-Homoalanyl PNAs: Synthesis and Indication of Higher Ordered Structures

Self-pairing complexes with extraordinarily high stability are formed by β-PNAs with four to six units of the nucleo-β-amino acid 1 . The key step in the synthesis is a Mitsunobu reaction between a β-homoserine and a purine derivative.     

Totalsynthese von Steroiden. 1. Mitteilung. rac-17β-Hydroxydes-A-androst-9-en-5-on

In connection with earlier work on the synthesis of 9β, 10α-steroids, a new and practical synthesis of rac-17α-hydroxy-des-A-androst-9-en-5-one ( 19 ) has been developed, based on a novel stereoselective condensation of 7-hydroxy-1-nonen-3-one ( 3 ) with 2-methyl-cyclopentane-1, 3-dione ( 9 ) and subsequent transformations of the resulting tricyclic diene ether 12 .     

Total Synthesis of β-Bulnesene and 1-Epi-β-bulnesene by Intramolecular Photoaddition

dl-β-Bulnesene (1) and dl-1-epi-α-bulnesene (15) have been synthesized starting from the bromide 4 (Schemes 2 and 3). In the key step 9→10 the bonds of the final product were formed by an intramolecular photoaddition. The synthesis was completed by the fragmentation 12→14 and the Wittig reaction 14→15+1 .