Stereoselective Total Synthesis of Botryolide E

The stereoselective total synthesis of the naturally occurring γ‐lactone derivative botryolide E ( 1 ) was accomplished with acetaldehyde as the starting material (Scheme 2). The asymmetric allyl boration, asymmetric dihydroxylation, chelation‐mediated diastereoselective vinylation, and ring‐closing metathesis reaction are the key steps. The method can conveniently be utilized for the preparation of other related γ‐lactone derivatives.     

Guianolactones A and B,Two Rearranged Pentacyclic Limonoids from the Seeds of Carapa guianensis

Two novel rearranged limonoids, guianolactones A ( 1 ) and B ( 2 ), were isolated from Carapa guianensis Aubl. (Meliaceae) seeds. The structures of 1 and 2 with their absolute configurations were elucidated in detailed examinations using single‐crystal X‐ray diffraction analyses and 2D NMR spectra. Guianolactone A ( 1 ) has a novel 5/6/6/6/6 pentacyclic core including two δ ‐lactone and a tetrahydropyran ring, while guianolactone B ( 2 ) is a novel limonoid with a 6/6/5/6/6 pentacyclic core featuring a δ ‐lactone and a tetrahydrofuran ring.     

Sesquiterpenoids and Phenylpropane Derivatives from Sonchus uliginosus

Six new compounds were isolated from the whole plant of Sonchus uliginosus, including three eudesmane‐type sesquiterpenoids (1β,6α)‐1,6,14‐trihydroxyeudesm‐3‐en‐12‐oic acid γ‐lactone ( 1 ), (1β,6α)‐1,6,14‐trihydroxyeudesma‐3,11(13)‐dien‐12‐oic acid γ‐lactone ( 2 ), and (1β,6α)‐1,6‐dihydroxy‐14‐O‐[(4‐hydroxyphenyl)acetyl]eudesma‐3,11(13)‐dien‐12‐oic acid γ‐lactone ( 3 ), and three phenylpropane derivatives, 4‐hydroxy‐γ,3,5‐trimethoxybenzenepropanol ( 6 ), γ,3,4,5‐tetramethoxybenzenepropanol ( 7 ), and γ,3,4,5‐tetramethoxybenzenepropanol acetate ( 8 ), together with the two known compounds 4 and 5 . The new structures were elucidated by means of spectroscopic methods, such as IR, EI‐MS, HR‐ESI‐MS, 1D‐ and 2D‐NMR, and by comparison of the spectroscopic data with those reported for structurally related compounds.     

Menverins A–D,New Highly Oxygenated Guaiane Lactones from Hainan Gorgonian Menella verrucosa (Brundin)

Four new highly oxygenated guaiane lactones, menverins A–D ( 1 – 4 ), were isolated from the gorgonian Menella verrucosa (Brundin ) from the South China Sea. Their structures and relative configurations were elucidated on the basis of spectroscopic data. All compounds contain a conjugated α‐methyl‐substituted α, β‐unsaturated γ‐lactone moiety, a C(8)?C(9) conjugated with the γ‐lactone moiety, and an exocyclic methylene group at C(4) (trivial numbering).     

Formal Total Synthesis of (−)‐Apicularen A by a Strategy Based on Ring‐Closing Metathesis and Transannular Cyclization

A formal synthesis of (?)‐apicularen A, a potent antitumor agent with unique biological properties, has been completed in a 15‐step sequence starting from a known, enantiomerically pure hydroxyepoxide, which was generated by using the Jacobsen hydrolytic‐kinetic‐resolution methodology. The 12‐membered macrocyclic lactone in the target was constructed by ring‐closing metathesis, and the trans‐tetrahydropyran ring system was created through the transannular etherification of a hydroxyalkene.     

Synthesis of New Furo[3,4‐b]quinolin‐1(3H)‐one Scaffolds Derived from γ‐Lactone‐Fused Quinolin‐4(1H)‐ones

In the context of our aim of discovering new antitumor drugs among synthetic γ‐lactone‐ and γ‐lactam‐fused 1‐methylquinolin‐4(1H)‐ones, we developed a rapid access to 5‐methyl‐1,3‐dioxolo[4,5‐g]furo[3,4‐b]quinoline‐8,9(5H,6H)‐dione ( 9 ) exploiting the γ‐lactone‐fused chloroquinoline 10 previously synthesized in our laboratory (Scheme 1). We also elaborated efficient synthetic methods allowing for a rapid access to two nonclassical bioisosteres of 9 , i.e., a deoxy and a carba analogue. The deoxy analogue 11 was prepared in two steps from the γ‐lactone‐fused quinoline 13 which was also the synthetic precursor of 10 (Scheme 1). The carba analogue 6,9‐dihydro‐5‐methyl‐9‐methylene‐1,3‐dioxolo[4,5‐g]furo[3,4‐b]quinolin‐8(5H)‐one ( 12 ) was easily prepared by HCl elimination from the 9‐(chloromethyl)dioxolofuroquinoline 15 , which was obtained via a three‐component one‐pot reaction from N‐methyl‐3,4‐(methylenedioxy)aniline (=N‐methyl‐1,3‐benzodioxol‐5‐amine; 16 ), commercially available chloroacetaldehyde, and tetronic acid ( 17 ) (Scheme 2).     

Novel Concise Synthesis of (-)-Clausenamide

A six‐step synthesis of (?)‐clausenamide is described. Optically pure (R,E)‐1,3‐diphenylallylic alcohol was acetylated and then subjected to an Ireland‐Claisen rearrangement, giving the γ,δ‐unsaturated acid, which underwent a substrate‐induced stereoselective bromolactonization to afford the expected all‐equatorial substituted bromo‐δ‐lactone. An unusual chemo‐selective aminolysis of the lactone resulted in the formation of a γ,δ‐epoxy‐amide in stereospecific manner. Base‐promoted cyclization of this intermediate and the subsequent Davis oxidation furnished the synthesis, delivering the final product in >99% ee and up to 34% overall yield.     

Ypsilactosides A and B,Two New C22‐Steroidal Lactone Glycosides from Ypsilandra thibetica

Two new C₂₂‐steroidal lactone glycosides, ypsilactosides A ( 1 ) and B ( 2 ), were isolated from the EtOH extract of the whole plant of Ypsilandra thibetica. Their structures were established as (3β,5α,16β,20S)‐3,16‐dihydroxy‐6‐oxopregnane‐20‐carboxylic acid γ‐lactone 3‐(β‐D ‐glucopyranoside) ( 1 ) and (3β,16β)‐3,16‐dihydroxypregna‐5,20‐diene‐20‐carboxylic acid γ‐lactone 3‐{O‐α‐L ‐rhamnopyranosyl‐(1→4)‐O‐α‐L ‐rhamnopyranosyl‐(1→4)‐O‐[α‐L ‐rhamnopyranosyl‐(1→2)]‐β‐D ‐glucopyranoside} ( 2 ) on the basis of extensive spectroscopic analyses and chemical degradations.     

Three Novel Compounds from the Flowers of Bombax malabaricum

Two unusual 9′‐norneolignans, bombasin ( 1 ) and bombasin 4‐O‐β‐glucoside ( 2 ), and a novel D ‐gulono‐γ‐lactone derivative, bombalin ( 3 ), were isolated from the flowers of Bombax malabaricum, together with the three known compounds dihydrodehydrodiconiferyl alcohol 4‐O‐β‐D ‐glucopyranoside ( 4 ), trans‐3‐(p‐coumaroyl)quinic acid ( 5 ), and neochlorogenic acid ( 6 ). Their structures were elucidated by extensive spectroscopic methods as well as chemical transformation. Compounds 1 – 3 were evaluated against the HGC‐27 gastrointestinal and Hela cervical human cancer cell lines, but all were inactive in both lines (IC₅₀>50 μM ).     

Tropone Is a Mere Ketone for Cycloadditions to Ketenes

Tropone ( 1 ) reacts with ketenes 2 to yield [8+2] cycloadducts, the γ‐lactones 3 . The concerted [8+2] cycloaddition path is formally symmetry‐allowed, but we established that it is unfavorable. Careful low‐temperature NMR (¹H, ¹³C, and ¹⁹F) spectroscopies of the reaction of diphenyl ketene ( 2b ) or bis(trifluoromethyl) ketene ( 2c ) with tropone ( 1 ) allowed the direct detection of a β‐lactone intermediates 5b , c and novel norcaradiene species 6b , c in head‐to‐head configurations. The [2+2] cycloadducts 5b , c equilibrated with the norcaradienes 6b , c . The β‐lactones 5b and 5c were converted to the γ‐lactones 3b and 3c , respectively, in quantitative yields. The DFT calculations showed that the concerted [8+2] cycloaddition is unfavorable. The first step of the calculated reaction 1 + 2c is a cycloaddition which leads to a dioxetane intermediate. This initial [2+2] cycloadduct is isomerized to the β‐lactone 5c via the first zwitterionic intermediate. The β‐lactone 5c is further isomerized to the product γ‐lactone 3c via the second zwitterion intermediate. Thus, 3c is not formed via the well‐established two‐step mechanism including zwitterionic intermediates but via a five‐step mechanism composed of a [2+2] cycloaddition and subsequent isomerization (Scheme 12).     

Verticillane and Norverticillane Diterpenoids from the Formosan Soft Coral Cespitularia hypotentaculata

Five new diterpenes, cespihypotins W–Z ( 1 – 4 , resp.) and cespihypotone ( 5 ) have been isolated from the AcOEt‐soluble fraction of the Formosan soft coral Cespitularia hypotentaculata. Two of them having the norverticillane skeleton, i.e., 1 and 2 , and the other three, 3 – 5 , possessing a verticillane skeleton. The structures were established as (+)‐(1βH,7E)‐6β,11β‐dihydroxynorverticilla‐4(18),7‐diene‐10,12‐dione ( 1 ), (+)‐(1βH,7E)‐6β‐acetoxy‐11β‐hydroxynorverticilla‐4(18),7‐diene‐10,12‐dione ( 2 ), (?)‐(1βH,7E)‐6β‐acetoxyverticilla‐4(18),7,11‐triene‐10,12‐γ‐lactone ( 3 ), (+)‐(1βH,7E)‐6β‐acetoxy‐10‐hydroxyverticilla‐4(18),7,11‐triene‐10,12‐γ‐lactone ( 4 ), and (+)‐(1βH,3Z)‐10β‐hydroxy‐6‐oxoverticilla‐3,11‐diene‐10,12‐γ‐lactone ( 5 ), respectively, on the basis of 1D‐ and 2D‐NMR spectroscopic analyses.     

A Novel Atisane Diterpenoid from Spiraea japonica var. acuta

A novel ent‐atisane lactone, spiramilactone E ( 1 ), was isolated from Spiraea japonica var. acuta Yu . Its structure was elucidated by extensive spectroscopic analyses, and unequivocally confirmed by single‐crystal X‐ray diffraction (Fig. 2). Compound 1 contains a γ‐lactone moiety between the 6‐OH function and C(20), and β‐configuration for the 7‐OH group, in contrast to known related diterpenes previously isolated from the S. japonica complex.     

Two Unusual Xanthones from the Bark of Garcinia xanthochymus

A new xanthone derivative, garcinexanthone F ( 1 ), which was found to possess an α,β‐unsaturated γ‐lactone moiety, and a new bisxanthone, bigarcinenone B ( 2 ), with a terpene bridge providing the xanthone? xanthone linkage, were isolated from the bark of Garcinia xanthochymus. Their structures were elucidated by spectroscopic methods, especially 2D‐NMR techniques. The antioxidant assay in vitro showed that compounds 1 and 2 exhibited significant scavenging activities against 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) radical with IC₅₀ values of 22.32 and 20.14 μM , and against HO^. radical with IC₅₀ values of 1.16 and 2.85 μM , respectively.     

Stereoselective Synthesis and Physicochemical Properties of Liquid‐Crystal Compounds Possessing a trans‐2,5‐Disubstituted Tetrahydropyran Ring with Negative Dielectric Anisotropy

Three stereoselective syntheses and the physicochemical properties of trans,trans‐5‐(4‐ethoxy‐2,3‐difluorophenyl)‐2‐(4‐propylcyclohexyl)tetrahydropyran, which is an important liquid‐crystal compound with a large negative dielectric anisotropy (Δε=?7.3), are described. The key step in the construction of the trans‐2,5‐disubstituted tetrahydropyran ring in the first approach involved a benzylic cation mediated intramolecular olefin cyclization of a 2‐allyloxy‐1‐arylethanol derivative. The second method included the Et₂Zn‐induced 1,2‐aryl shift of a bromohydrin obtained from a hetero‐Diels–Alder reaction, followed by stereoselective bromination. The third approach utilized the hetero‐Diels–Alder reaction of trans‐4‐propylcyclohexanecarboxaldehyde and a 2‐aryl‐3‐(trimethylsilyl)oxy‐1,3‐butadiene, followed by stereoselective protonation. From results obtained by using a quantum chemical calculation method, the reason why the target compound shows a large negative Δε value is discussed.     

A Short Synthesis of Clionamine D

Herein we describe a scalable four‐step preparation of α‐methylene‐γ‐lactone 3 from steroidal sapogenin. This method allowed a facile synthesis of clionamine D, a natural aminosteroid with potent autophagy bioactivity and unprecedented chemical structure.     

Chemo‐Enzymatic Synthesis and Determination of the Absolute Configuration of Both Enantiomers of Methyl trans‐5‐Oxo‐2‐pentylpyrrolidine‐3‐carboxylate Precursors of the Aza Analogues of (+)‐ and (−)‐Methylenolactocin

Enantiomerically pure methyl esters of (+)‐(2R,3S)‐ and (−)‐(2S,3R)‐5‐oxo‐2‐pentylpyrrolidine‐3‐carboxylic acid with 99% and 98% ee were obtained by enzymatic resolution of the corresponding racemic mixture using α‐chymotrypsin and pig‐liver acetone powder, respectively. Their absolute configurations were established by chemical methods, i.e., conversion of the trans‐γ‐lactam moiety to the corresponding γ‐lactone of known configuration. The favorable interactions between the trans‐γ‐lactam and α‐chymotrypsin were rationalized by molecular‐mechanics calculations, which suggest a different situation for the cis‐diastereoisomer.     

Stereoselective Synthesis of 1,2,3‐Triazolooxazine and Fused 1,2,3‐Triazolo‐δ‐Lactone Derivatives

The stereoselective synthesis of 1,2,3‐triazolooxazine and fused 1,2,3‐triazolo‐δ‐lactone by applying chemoenzymatic methods is described. trans‐2‐Azidocyclohexanol was successfully resolved by Novozyme 435 with an ee value of 99%. Installation of the alkyne moiety on the enantiomerically enriched azidoalcohol by O‐alkylation, followed by intramolecular azide? alkyne [3+2] cycloaddition resulted in the desired 1,2,3‐triazolooxazine derivative. Enantiomerically pure azidocyclohexanol was also subjected to the Huisgen 1,3‐dipolar cycloaddition reaction with dimethylacetylene dicarboxylate, followed by intramolecular cyclization of the corresponding cycloadduct, to furnish a fused 1,2,3‐triazolo‐δ‐lactone.     

Four New Eudesmane Sesquiterpenoid Lactones from Chloranthus serratus

Four new eudesmane sesquiterpenoids endowed with an α,β‐unsaturated γ‐lactone five‐membered ring, serralactones A–D ( 1 – 4 , resp.), along with seven known sesquiterpenoids, were isolated from the whole plant Chloranthus serratus. Their structures and relative configurations were established on the basis of extensive spectroscopic analyses.     

Adenanthusone,a New Ursane Type Nortriterpenoid from Isodon adenanthus

A new ursane‐type nortriterpenoid, adenanthusone (=(11α,12α)‐4‐demethyl‐11,12‐epoxy‐3,13‐dihydroxy‐2‐oxoursa‐3,20(30)‐diene‐28‐oic acid γ‐lactone; 1 ) was isolated from Isodon adenanthus. Its structure was determined by NMR spectra and X‐ray crystallographic diffraction analysis. The biogenetic implication of the nortriterpene is discussed.     

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.