Synthesis and Cytotoxicity Evaluation of Certain α‐Methylidene‐ γ‐butyrolactones Bearing Coumarin,Flavone, Xanthone,Carbazole, and Dibenzofuran Moieties

The cytotoxicities of α‐methylidene‐γ‐butyrolactones, which are linked to coumarins (see 15 and 16 ) and to potential DNA‐intercalating carriers such as flavones, xanthones, carbazole, and dibenzofuran (see 9a – e , 10a – e , 11 , and 12 ), were studied. These compounds were synthesized via alkylation of their hydroxy precursors followed by a Reformatsky‐type condensation (Scheme). These α‐methylidene‐γ‐butyralactones were evaluated in vitro against 60 human tumor cell lines derived from nine cancer cell types and demonstrated a strong growth‐inhibitory activity against leukemia cancer cells (Tables 1 and 2). For flavone‐ and xanthone‐containing α‐methylidene‐γ‐butyrolactones 9a – e and 10a – e , respectively, the overall potency (mean value) decreased on introduction of an electron‐withdrawing substituent at the γ‐phenyl substituent and increased with an electron‐donating substituent. Comparing the different chromophores established the following order of decreasing potency (log GI₅₀): dibenzofuran ( 12 , −6.17) > flavone ( 9a , −5.96) > carbazole ( 11 , −5.80) and xanthone ( 10a , −5.77) > coumarin ( 15 , −5.60; 16 , −5.65). Among them, the dibenzofuran derivative 12 showed not only strong inhibitory activities against leukemia cancer cell lines with an average log GI₅₀ value of −7.22, but also good inhibitory activities against colon, melanoma, and breast cancer cells with average log GI₅₀ values of −6.23, −6.31, and −6.39, respectively.     

Facile Synthesis of 5‐Hexyl‐4‐methyl‐γ‐butyrolactone via Nef Reaction as a Key Step

A racemic cis/trans mixture of 5‐hexyl‐4‐methyl‐γ‐butyrolactone was easily synthesized from 1‐iodoheptane in four steps with inexpensive and readily available reagents. Our new synthesis method can be potentially employed for mass production of the 4‐methyl‐5‐hexyl‐γ‐butyrolactone as well as other poly‐alkyl substituted γ‐butyrolactones.     

An NHC‐Catalyzed In Situ Activation Strategy to β‐Functionalize Saturated Carboxylic Acid: An Enantioselective Formal [3+2] Annulation for Spirocyclic Oxindolo‐γ‐butyrolactones

An in situ NHC‐catalyzed activation strategy to β‐functionalize saturated carboxylic acid was developed. This asymmetric formal [3+2] annulation could deliver spirocyclic oxindolo‐γ‐butyrolactones from saturated carboxylic acid and isatin in good yields with high to excellent enantioselectivities. The easy availability of the starting materials, direct installation of functional units at unreactive carbon atom and the convergent assembly make this protocol attractive in the field of organic synthesis.     

Pseudonocardides A – G,New γ‐Butyrolactones from Marine‐derived Pseudonocardia sp. YIM M13669

Seven new γ‐butyrolactones, named pseudonocardides A – G ( 1  –  7 ), were isolated from the marine‐derived actinomycete strain Pseudonocardia sp. YIM M13669. Their structures were elucidated on the basis of spectroscopic data including 1D‐ and 2D‐NMR, and HR‐ESI‐MS. The absolute configuration of 1 was determined by X‐ray crystallographic analysis of 1a (4‐bromobenzoate derivative of 1 ). The antibacterial activity against Mycobacterium smegmatis MC²155 and cytotoxicities of compounds 1  –  7 were evaluated in this study.     

Synthesis and Antitumor Activity Evaluation of γ-Monofluorinated and γ,γ-Difluorinated Goniothalamin Analogues

A series of novel γ,γ‐difluorinated Goniothalamin analogues 4a – 4i and 6a – 6i were synthesized. The key steps included the construction of C‐5 stereocenter adjacent to gem‐difluoromethylene group by way of lipase AK catalyzed kinetic resolution, the introduction of aryl group via Stille coupling, and lactonization by 1,5‐oxidative cyclization. These γ,γ‐difluorinated Goniothalamin analogues 4a – 4i and their enantiomers 6a – 6i , together with several corresponding γ‐monofluorinated Goniothalamin analogues were biologically evaluated against four different cancer cell lines. Compound 7h showed a nearly equivalent potency as the parent (R)‐Goniothalamin in the micromolar range. The different fluorine effects between fluoromethylene and gem‐difluoromethylene on antitumor activity were discussed through the analysis of bioassay data.     

金属参与的N-酰基腙的偕二氟烯丙基化反应：高效合成偕二氟高烯丙基胺

金属铟参与醛衍生的N-酰基腙 1a-1q,4a-4g与3-溴-3,3-二氟丙烯 2 的反应,分别高效得到α, α-二氟高烯丙基肼 3a-3q,5a-5g。该反应条件温和,操作简便。硝基,酚羟基,苄氧基,α, β-不饱和醛的碳-碳双键等官能团对该反应具有良好的官能团兼容性。通过用锌粉代替铟粉, 酮衍生的N-酰基腙 6a-6d 也能发生偕二氟烯丙基化反应,以中等产率得到α, α-二氟高烯丙基肼 7a-7d。裂解肼3a的 N-N键顺利得到偕二氟高烯丙基胺 8,化合物 8 经丙烯酰化,随后进行RCM关环反应,可以方便的转化为偕二氟-γ-取代α, β-不饱和内酰胺 11。     

Synthesis of Halogenated α,β‐Unsaturated γ‐Butyrolactone Derivatives by Triphenylphosphine‐Catalyzed Cyclization of α‐Halogeno Ketones with Dialkyl Acetylenedicarboxylates (=Dialkyl But‐2‐ynedioates)

A Ph₃P‐catalyzed cyclization of α‐halogeno ketones 2 with dialkyl acetylenedicarboxylates (=dialkyl but‐2‐ynedioates) 3 produced halogenated α,β‐unsaturated γ‐butyrolactone derivatives 4 in good yields (Scheme 1, Table). The presence of electron‐withdrawing groups such as halogen atoms at the α‐position of the ketones was necessary in this reaction. Cyclization of α‐chloro ketones resulted in higher yields than that of the corresponding α‐bromo ketones. Dihalogeno ketones similarly afforded the expected γ‐butyrolactone derivatives in high yields.     

Intramolecular Photocyclization of 2‐Acylphenyl Methacrylates: a Convenient Access to 4,5‐Dihydro‐1,4‐epoxy‐2‐benzoxepin‐3(1H)‐ones (= Benzo[c]‐6,8‐dioxabicyclo[3.2.1]octan‐7‐ones

The photochemical reactions of 2‐acylphenyl methacrylates (= 2‐acylphenyl 2‐methylprop‐2‐enoates) 1 were investigated. Irradiation of 2‐acylphenyl methacrylates 1a – d in MeCN gave the tricyclic lactones 2a – d in good yields, together with a small amount of O CO bond cleavage product, the 2‐acylphenols 3a – d (Scheme 2, Table). The formation of the tricyclic lactones 2 probably follows a mechanism involving a 1,7‐diradical through ζ‐H abstraction (1,8‐H transfer) by the excited carbonyl O‐atom (Scheme 3). Irradiation of 2‐acylphenyl tiglate (= 2‐acylphenyl (2E)‐2‐methylbut‐2‐enoate) 1e and 2‐acylphenyl methacrylates 1g – i , substituted by a MeO group (δ‐H) at the 3,5‐positions of the phenyl group, also gave the tricyclic lactones 2e and 2g – i , but in low yields. On the other hand, no H‐abstraction products were observed on irridation of 2‐(ethoxycarbonyl)phenyl methacrylate 1f , of 2‐acylphenyl methacrylate 1j which is substituted by a Me group (γ‐H) at the 3,5‐positions of the phenyl group, and of 1k with an OH group at the 3‐position of the phenyl group.     

Regio‐ and Stereoselective Reductive Coupling of Bicyclic Alkenes with Propiolates Catalyzed by Nickel Complexes: A Novel Route to Functionalized 1,2‐Dihydroarenes and γ‐Lactones

7‐Oxabenzonorbornadienes derivatives 1 a – d underwent reductive coupling with alkyl propiolates CH₃C?CCO₂CH₃ ( 2 a ), PhC?CCO₂Et ( 2 b ), CH₃(CH₂)₃C?CCO₂CH₃ ( 2 c ), CH₃(CH₂)₄C?CCO₂CH₃ ( 2 d ), TMSC?CCO₂Et ( 2 e ), (CH₃)₃C?CCO₂CH₃ ( 2 f ) and HC?CCO₂Et ( 2 g ) in the presence of [NiBr₂(dppe)] (dppe=Ph₂PCH₂CH₂PPh₂), H₂O and zinc powder in acetonitrile at room temperature to afford the corresponding 2alkenyl‐1,2‐dihydronapthalen‐1‐ol derivatives 3 a – n with remarkable regio‐ and diastereoselectivity in good to excellent yields. Similarly, the reaction of 7azabenzonorbornadienes derivative 1 e with propiolates 2 a, b and d proceeded smoothly to afford reductive coupling products 2alkenyl‐1,2‐dihydronapthalene carbamates 3 o – p in good yields with high regio‐ and stereoselectivity. This nickel‐catalyzed reductive coupling can be further extended to the reaction of 7oxabenzonorbornene derivatives. Thus, 5,6‐di(methoxymethyl)‐7‐oxabicyclo[2.2.1]hept‐2‐ene ( 4 ) reacted with 2 a and 2 d to furnish cyclohexenol derivatives bearing four cis substituents 5 a and b in 81 and 84 % yield, respectively. In contrast to the results of 4 with 2 , the reaction of dimethyl 7oxabicyclo[2.2.1]hept‐5‐ene‐2,3‐dicarboxylate ( 6 ) with propiolates 2 a – d afforded the corresponding reductive coupling/cyclization products, bicyclo[3.2.1]γ‐lactones 7 a – d in good yields. The reaction provides a convenient one‐pot synthesis of γ‐lactones with remarkably high regio‐ and stereoselectivity.     

Alkyne‐Mediated Approach to the Synthesis of (4R,5R)‐5‐Hydroxy‐4‐decanolide and (−)‐Muricatacin

The asymmetric synthesis of two naturally occurring 5‐hydroxy‐γ‐butyrolactones, (4R,5R)‐5‐hydroxy‐4‐decanolide ( 1a ) and (?)‐muricatacin ( 2 ), is described using a general alkyne‐mediated strategy. The key steps involved are Sonogashira coupling for the desired carbon‐chain extension followed by Sharpless asymmetric dihydroxylation to construct the hydroxy‐lactone framework.     

Synthesis and Cytotoxic Activities of α‐Methylidene‐γ‐butyrolactones Bearing a Quinolin‐4(1H)‐one Moiety

The cytotoxicities of the α‐methylidene‐γ‐butyrolactones 4 , 5 , and 8 , which are linked to a quinolin‐4(1H)‐one moiety through a piperazine or O‐atom bridge were studied. These compounds were synthesized by alkylation of 1‐ethyl‐6‐fluoro‐1,4‐dihydro‐7‐hydroxy‐4‐oxoquinoline‐3‐carboxylic acid ( 6 ) followed by a Reformatsky‐type condensation. Compounds 4 , 5 , and 8 were evaluated in vitro against 60 human‐tumor cell lines derived from nine cancer‐cell types and demonstrated not only strong growth‐inhibitory activities against leukemia cancer cells, but also fairly good activities against the growth of certain solid tumors (see Table). The O‐bridged derivatives 8a and 8b exhibit both cytostatic (mean log GI₅₀=−5.20 and −5.82, resp.) and cytocidal (mean log LC₅₀=−4.30 and −4.93, resp.) effects, while the piperazine‐bridged analogues 4 and 5 possess only weak cytostatic (mean log GI₅₀=−5.19 and −4.74, resp.; mean log LC₅₀>−4.00) capability. Among them, 8b is the most potent, with log GI₅₀=−6.47, −6.72, −6.53, and −6.52 against leukemia, SW‐620 (colon), Lox IMV1, and SK‐MEL‐28 (melanoma) cancer cells, respectively.     

Enzyme‐Mediated Preparation of (+)‐ and (−)‐β‐Irone and (+)‐ and (−)‐cis‐γ‐Irone from Irone alpha®

The (−)‐ and (+)‐β‐irones ((−)‐ and (+)‐ 2 , resp.), contaminated with ca. 7 – 9% of the (+)‐ and (−)‐trans‐α‐isomer, respectively, were obtained from racemic α‐irone via the 2,6‐trans‐epoxide (±)‐ 4 (Scheme 2). Relevant steps in the sequence were the LiAlH₄ reduction of the latter, to provide the diastereoisomeric‐4,5‐dihydro‐5‐hydroxy‐trans‐α‐irols (±)‐ 6 and (±)‐ 7 , resolved into the enantiomers by lipase‐PS‐mediated acetylation with vinyl acetate. The enantiomerically pure allylic acetate esters (+)‐ and (−)‐ 8 and (+)‐ and (−)‐ 9 , upon treatment with POCl₃/pyridine, were converted to the β‐irol acetate derivatives (+)‐ and (−)‐ 10 , and (+)‐ and (−)‐ 11 , respectively, eventually providing the desired ketones (+)‐ and (−)‐ 2 by base hydrolysis and MnO₂ oxidation. The 2,6‐cis‐epoxide (±)‐ 5 provided the 4,5‐dihydro‐4‐hydroxy‐cis‐α‐irols (±)‐ 13 and (±)‐ 14 in a 3 : 1 mixture with the isomeric 5‐hydroxy derivatives (±)‐ 15 and (±)‐ 16 on hydride treatment (Scheme 1). The POCl₃/pyridine treatment of the enantiomerically pure allylic acetate esters, obtained by enzymic resolution of (±)‐ 13 and (±)‐ 14 , provided enantiomerically pure cis‐α‐irol acetate esters, from which ketones (+)‐ and (−)‐ 22 were prepared (Scheme 4). The same materials were obtained from the (9S) alcohols (+)‐ 13 and (−)‐ 14 , treated first with MnO₂, then with POCl₃/pyridine (Scheme 4). Conversely, the dehydration with POCl₃/pyridine of the enantiomerically pure 2,6‐cis‐5‐hydroxy derivatives obtained from (±)‐ 15 and (±)‐ 16 gave rise to a mixture in which the γ‐irol acetates 25a and 25b and 26a and 26b prevailed over the α‐ and β‐isomers (Scheme 5). The (+)‐ and (−)‐cis‐γ‐irones ((+)‐ and (−)‐ 3 , resp.) were obtained from the latter mixture by a sequence involving as the key step the photochemical isomerization of the α‐double bond to the γ‐double bond. External panel olfactory evaluation assigned to (+)‐β‐irone ((+)‐ 2 ) and to (−)‐cis‐γ‐irone ((−)‐ 3 ) the strongest character and the possibility to be used as dry‐down note.     

Diastereoselective Electrophilic Amination of Chiral 1‐Benzoyl‐2,3,5,6‐tetrahydro‐3‐methyl‐2‐(1‐methylethyl)pyrimidin‐4(1H)‐one for the Asymmetric Syntheses of α‐Substituted α,β‐Diaminopropanoic Acids

The chiral compounds (R)‐ and (S)‐1‐benzoyl‐2,3,5,6‐tetrahydro‐3‐methyl‐2‐(1‐methylethyl)pyrimidin‐4(1H)‐one ((R)‐ and (S)‐ 1 ), derived from (R)‐ and (S)‐asparagine, respectively, were used as convenient starting materials for the preparation of the enantiomerically pure α‐alkylated (alkyl=Me, Et, Bn) α,β‐diamino acids (R)‐ and (S)‐ 11 – 13 . The chiral lithium enolates of (R)‐ and (S)‐ 1 were first alkylated, and the resulting diasteroisomeric products 5 – 7 were aminated with ‘di(tert‐butyl) azodicarboxylate’ (DBAD), giving rise to the diastereoisomerically pure (≥98%) compounds 8 – 10 . The target compounds (R)‐ and (S)‐ 11 – 13 could then be obtained in good yields and high purities by a hydrolysis/hydrogenolysis/hydrolysis sequence.     

Design,Synthesis, NMR‐Solution and X‐Ray Crystal Structure of N‐Acyl‐γ‐dipeptide Amides That Form a βII′‐Type Turn

Conformational analysis of γ‐amino acids with substituents in the 2‐position reveals that an N‐acyl‐γ‐dipeptide amide built of two enantiomeric residues of unlike configuration will form a 14‐membered H‐bonded ring, i.e., a γ‐peptidic turn (Figs. 1 – 3). The diastereoselective preparation of the required building blocks was achieved by alkylation of the doubly lithiated N‐Boc‐protected 4‐aminoalkanoates, which, in turn, are readily available from the corresponding (R)‐ or (S)‐α‐amino acids (Scheme 1). Coupling two such γ‐amino acid derivatives gave N‐acetyl and N‐[(tert‐butoxy)carbonyl] (Boc) dipeptide methyl amides ( 1 and 10 , resp.; Fig. 2, Scheme 2); both formed crystals suitable for X‐ray analysis, which confirmed the turn structures in the solid state (Fig. 4 and Table 4). NMR Analysis of the acetyl derivative 1 in CD₃OH, with full chemical‐shift and coupling assignments, and, including a 300‐ms ROESY measurement, revealed that the predicted turn structure is also present in solution (Fig. 5 and Tables 1 – 3). The results described here are yet another piece of evidence for the fact that more stable secondary structures are formed with a decreasing number of residues, and with increasing degree of predictability, as we go from α‐ to β‐ to γ‐peptides. Implications of the superimposable geometries of the actual turn segments (with amide bonds flanked by two quasi‐equatorial substituents) in α‐, β‐, and γ‐peptidic turns are discussed.     

A Mild Approach to the Synthesis of sn‐Glycerol 1,2‐Di‐γ‐linolenate 3‐Palmitate

A synthetic approach comprising several studied modifications was applied to the preparation of sn‐glycerol 1,2‐di‐γ‐linolenate 3‐palmitate ( 4 ). Thereby, a convenient and mild synthetic method was elaborated, affording 4 from 1,2‐O‐isopropylidene‐sn‐glycerol ( 1 ) in an average yield of 65 – 75% and analytically acceptable purity.     

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.     

Synthesis and Characterization of New Thebaine Derivatives as Potential Opioid Agonists and Antagonists: 2‐[N‐(1H‐Tetrazol‐5‐yl)‐6,14‐endo‐etheno‐6,7,8,14‐tetrahydrothebaine‐7α‐yl]‐5‐phenyl‐1,3,4‐oxadiazoles

In this study, we report the synthesis a series of novel 2‐[N‐(1H‐tetrazol‐5‐yl)‐6,14‐endo‐etheno‐6,7,8,14‐tetrahydrothebaine‐7α‐yl]‐5‐phenyl‐1,3,4‐oxadiazole derivatives ( 7a – e ) which have potential opioid antagonist and agonist. The substitution reaction of 6,14‐endo‐ethenotetrahydrothebaine‐7α‐carbohydrazide with corresponding benzoyl chlorides gave diacylhydrazine compounds 4a – e in good yields. The treatment of compounds 4a – e with POCl₃ caused the conversion of side‐chain of compounds 5a – e into 1,3,4‐oxadiazole ring at C(7) position; thus, compounds 5a – e were obtained. Subsequently, cyanamides ( 6a – e ) were prepared from compounds 5a – e and then compounds 7a – e were synthesized by the azidation of 6a – e with NaN₃. The structures of the compounds were established on the basis of their IR, ¹H NMR, ¹³C APT, 2D‐NMR (COSY, NOESY, HMQC, HMBC) and high‐resolution mass spectral data.     

Synthesis and Antiplatelet‐Activity Evaluation of α‐Methylidene‐γ‐butyrolactones Bearing 3,4‐Dihydroquinolin‐2(1H)‐one Moieties

In continuation of our search for potent antiplatelet agents, we have synthesized and evaluated several α‐methylidene‐γ‐butyrolactones bearing 3,4‐dihydroquinolin‐2(1H)‐one moieties. O‐Alkylation of 3,4‐dihydro‐8‐hydroxyquinolin‐2(1H)‐one ( 1 ) with chloroacetone under basic conditions afforded 3,4‐dihydro‐8‐(2‐oxopropoxy)quinolin‐2(1H)‐one ( 2a ) and tricyclic 2,3,6,7‐tetrahydro‐3‐hydroxy‐3‐methyl‐5H‐pyrido[1,2,3‐de][1,4]benzoxazin‐5‐one ( 3a ) in a ratio of 1 : 2.84. Their Reformatsky‐type condensation with ethyl 2‐(bromomethyl)prop‐2‐enoate furnished 3,4‐dihydro‐8‐[(2,3,4,5‐tetrahydro‐2‐methyl‐4‐methylidene‐5‐oxofuran‐2‐yl)methoxy]quinolin‐2(1H)‐one ( 4a ), which shows antiplatelet activity, in 70% yield. Its 2′‐Ph derivatives, and 6‐ and 7‐substituted analogs were also obtained from the corresponding 3,4‐dihydroquinolin‐2(1H)‐ones via alkylation and the Reformatsky‐type condensation. Of these compounds, 3,4‐dihydro‐7‐[(2,3,4,5‐tetrahydro‐4‐methylidene‐5‐oxo‐2‐phenylfuran‐2‐yl)methoxy]quinolin‐2(1H)‐one ( 10b ) was the most active against arachidonic acid (AA) induced platelet aggregation with an IC₅₀ of 0.23 μM . For the inhibition of platelet‐activating factor (PAF) induced aggregation, 6‐{[2‐(4‐fluorophenyl)‐2,3,4,5‐tetrahydro‐4‐methylidene‐5‐oxofuran‐2‐yl]methoxy}‐3,4‐dihydroquinolin‐2(1H)‐one ( 9c ) was the most potent with an IC₅₀ value of 1.83 μM .     

Synthesis of Some Novel Phenyl Substituted Oxothiazolidin- 1’’,3’’,4’’-thiadiazolo-[3’,4’-b]thiazoline of 3β-Substituted Cholestane

Three title compounds 4a—4c have been synthesized by the cyclodehydration of 1’-benzylidine-4’-(3β-substituted-5α-cholestane-6-yl)thiosemicarbazones 2a—2c with thioglycolic acid followed by the treatment with cold conc. H2SO4 in dioxane. The compounds 2a—2c were prepared by condensation of 3β-substituted-5α-cholestan- 6-one-thiosemicarbazones 1a—1c with benzaldehyde. These thiosemicarbazones 1a—1c were obtained by the reaction of corresponding 3β-substituted-5α-cholestan-6-ones with thiosemicarbazide in the presence of few drops of conc. HCl in methanol. The structures of the products have been established on the basis of their elemental, analytical and spectral data.     

New Synthesis of Pyrrolidines via Reaction of γ‐Halocarbanions with Imines

γ‐Chlorocarbanions of proper nucleophilicity, generated from 3‐chloropropyl pentachlorophenyl sulfone (=pentachloro[(3‐chloropropyl)sulfonyl]benzene; 1 ; Ar=C₆Cl₅), add to electron‐deficient formal imines 3a – l to produce anionic adducts that enter intramolecular substitution leading to substituted pyrrolidines. This new and simple synthesis of pyrrolidines mimics a 1,3‐dipolar cycloaddition, although it proceeds in two distinct steps.