Mechanisms of DABCO‐ and DMAP‐catalyzed [2 + 4] cycloaddition reactions of methylallenoate with methyleneindolonone: A DFT study

The mechanisms and stereoselectivities of the [2 + 4] cycloaddition reaction of methylallenoate R1 with methyleneindolonone R2 catalyzed by DABCO (Equation 1) and DMAP (Equation 2) organocatalysts have been examined with density functional theory (M06‐2X) calculations. Several possible reaction pathways (paths 1a, 1b, and 1c for Equation 1 and paths 2a and 2b for Equation 2) were located and compared. The results of our study reveal that for both reactions, three reaction stages have been characterized: nucleophilic addition of the catalyst ( DABCO or DMAP ) to R1 (Stage I ), addition of the other reactant R2 (Stage II ), intramolecular cycloaddition and liberation of the catalyst ( DABCO or DMAP ) afforded the final product (Stage III ). For the DABCO ‐catalyzed cycloaddition, we predict that path 1a leading to P(E) is the most energy favorable pathway among the three possible pathways. The carbon–carbon bond formation step is the rate‐determining step (ΔG ^?=23.6 kcal/mol). With DMAP catalyst, the same reaction gave P(Z) as the major product. The barrier for the rate‐determining step (addition of R1 to DMAP ) is 25.8 kcal/mol. The calculated results are in agreement with the experimental findings. Moreover, for both reactions, the analysis of global reactivity indexes has been carried out to examine the role of catalyst. The present study should provide a general mechanistic framework for the rational design of this kind of reactions.     

Crystal Structure of Garciniaphenone and Evidences on the Relationship between Keto–Enol Tautomerism and Configuration

Garciniaphenone (=rel‐(1R,5R,7R)‐3‐benzoyl‐4‐hydroxy‐8,8‐dimethyl‐1,7‐bis(3‐methylbut‐2‐en‐1‐yl)bicyclo[3.3.1]non‐3‐ene‐2,9‐dione; 1 ), a novel natural product, was isolated from a hexane extract of Garcinia brasiliensis fruits. The crystal structure of 1 as well as the selected geometrical and configurational features were compared with those of known related polyprenylated benzophenones. Garciniaphenone is the first representative of polyprenylated benzophenones without a prenyl substituent at C(5). Notably, the absence of a 5‐prenyl substituent has an impact on the molecular geometry. The tautomeric form of 1 in the solid state was readily established by a residual‐electronic‐density map generated by means of a difference Fourier analysis, and there is an entirely delocalized six‐membered chelate ring encompassing the keto–enol moiety. The configuration at C(7) was used to rationalize the nature of the keto–enol tautomeric form within 1 . The intermolecular array in the network is maintained by nonclassical intermolecular H‐bonds.     

Perchloric Acid–Silica (HClO4⋅SiO2)‐Catalyzed Synthesis of 14‐Alkyl‐ or 14‐Aryl‐14H‐dibenzo[a,j]xanthenes and N‐[(2‐Hydroxynaphthalen‐1‐yl)methyl]amides

The synthesis of 14‐aryl‐ or 14‐alkyl‐14H‐dibenzo[a,j]xanthenes 3 involving the treatment of naphthalen‐2‐ol ( 1 ) with arenecarboxaldehydes or alkanals 2 in the presence of HClO₄?SiO₂ as a heterogeneous catalyst was achieved (Table 1), and this reaction was extended to the preparation of N‐[(2‐hydroxynaphthalen‐1‐yl)methyl]amides 5 by a three‐component reaction with urea ( 4a ) or an amide 4b – d as a third reactant (Table 2).     

One‐Pot Synthesis of 5,7,8,9,9a,10‐Hexahydro‐8‐thioxotetrahydropyrido[2,3‐d : 6,5‐d′]dipyrimidine‐2,4,6(1H,3H,5aH)‐triones via a Four‐Component Coupling Reaction of Aldehydes,Amines, Barbituric Acids,and Thiouracil

An efficient one‐pot approach to the synthesis of 5,7,8,9,9a,10‐hexahydro‐8‐thioxopyrido[2,3‐d : 6,5‐d′]dipyrimidine‐2,4,6(1H,3H,5aH)‐triones 5 via a four‐component reaction of an aldehyde 1 , an amine 2 , a barbituric acid 3 , and thiouracil ( 4 ) is reported for the first time. This new multicomponent reaction is accomplished in refluxing EtOH in the presence of tungstophosphoric acid (H₃PW₁₂O₄₀) as a catalyst. A variety of hexahydropyrido[2,3‐d : 6,5‐d′]dipyrimidinetrione derivatives were successfully synthesized in excellent yields with this protocol (Table 2).     

Petrorhagiosides A – D,New γ‐Pyrone Derivatives from Petrorhagia saxifraga Link

Four novel γ‐pyrone (=4H‐pyran‐4‐one) metabolites, petrorhagiosides A–D, along with four known analogs, have been isolated from the MeOH extract of Petrorhagia saxifraga, a perennial herbaceous plant typical of Mediterranean vegetation. The structures of the new compounds were established on the basis of extensive spectroscopic analyses including 1D‐ an 2D‐NMR (¹H,¹H‐DQ‐COSY, TOCSY, HSQC, CIGAR‐HMBC, and HSQC‐TOCSY) experiments.     

Phochinenins A – F,Dimeric 9,10‐Dihydrophenanthrene Derivatives,from Pholidota chinensis

Six new compounds, phochinenins A–F ( 1 – 6 ), dimerized from 9,10‐dihydrophenanthrene and dihydrostilbene through direct coupling or an oxygen bridge, along with eight known compounds, were isolated from the whole plants of Pholidota chinensis. Their structures were elucidated on the basis of extensive spectroscopic investigations (1D‐, 2D‐NMR, and HR‐EI‐MS).     

6‐(Diazomethyl)‐1,3‐bis(methoxymethyl)uracil,Synthesis and Transformation into Annulated Pyrimidinediones

6‐(Diazomethyl)‐1,3‐bis(methoxymethyl)uracil ( 5 ) was prepared from the known aldehyde 3 by hydrazone formation and oxidation. Thermolysis of 5 and deprotection gave the pyrazolo[4,3‐d]pyrimidine‐5,7‐diones 7a and 7b . Rh₂(OAc)₄ catalyzed the transformation of 5 into to a 2 : 1 (Z)/(E) mixture of 1,2‐diuracilylethenes 9 (67%). Heating (Z)‐ 9 in 12n HCl at 95° led to electrocyclisation, oxidation, and deprotection to afford 73% of the pyrimido[5,4‐f]quinazolinetetraone 12 . The Rh₂(OAc)₄‐catalyzed reaction of 5 with 3,4‐dihydro‐2H‐pyran and 2,3‐dihydrofuran gave endo/exo‐mixtures of the 2‐oxabicyclo[4.1.0]heptane 13 (78%) and the 2‐oxabicyclo[3.1.0]hexane 15 (86%), Their treatment with AlCl₃ or Me₂AlCl promoted a vinylcyclopropane–cyclopentene rearrangement, leading to the pyrano‐ and furanocyclopenta[1,2‐d]pyrimidinediones 14 (88%) and 16 (51%), respectively. Similarly, the addition product of 5 to 2‐methoxypropene was transformed into the 5‐methylcyclopenta‐pyrimidinedione 18 (55%). The Rh₂(OAc)₄‐catalyzed reaction of 5 with thiophene gave the exo‐configured 2‐thiabicyclo[3.1.0]hexane 19 (69%). The analoguous reaction with furan led to 8‐oxabicyclo[3.2.1]oct‐2‐ene 20 (73%), and the reaction with (E)‐2‐styrylfuran yielded a diastereoisomeric mixture of hepta‐1,4,6‐trien‐3‐ones 21 (75%) that was transformed into the (1E,4E,6E)‐configured hepta‐1,4,6‐trien‐3‐one 21 (60%) at ambient temperature.     

Cytotoxic Naphtho‐γ‐pyrones from the Mangrove Endophytic Fungus Aspergillus tubingensis (GX1‐5E)

Four new dimeric naphtho‐γ‐pyrones, named rubasperone D ( 1 ), rubasperone E ( 2 ), rubasperone F ( 3 ), and its atropisomer rubasperone G ( 4 ), together with four known monomeric naphtho‐γ‐pyrones, TMC 256 A1 ( 5 ), rubrofusarin B ( 6 ), fonsecin ( 7 ), and flavasperone ( 8 ), were isolated from the mangrove endophytic fungus Aspergillus tubingensis (GX1‐5E) cultivated in solid rice medium. Their structures were elucidated by spectroscopic methods, including IR, 1D‐ and 2D‐NMR, and MS. In the in vitro cytotoxicity assays, 5 displayed inhibitory activities against tumor cell lines of MCF‐7, MDA‐MB‐435, Hep3B, Huh7, SNB19, and U87 MG with IC₅₀ values between 19.92 and 47.98 μM . Compounds 1, 6 , and 8 also showed mild cytotoxic activity.     

Baimantuoluolines D – F,Three New Withanolides from the Flower of Datura metel L.

Three new withanolide compounds, named baimantuoluolines D–F, along with three known withanolides and a lignan were isolated from the flower of Datura metel L., the parts effective against psoriasis. The structures of the new compounds were elucidated as (5α,6β,12β,20R,22R,24R,25S)‐21,24‐epoxy‐5,6,12‐trihydroxy‐27‐methoxy‐1‐oxowith‐2‐enolide ( 1 ), (5α,6β,12β,20R,22R,24R,25S)‐21,24‐epoxy‐5,6,12,27‐tetrahydroxy‐1‐oxowith‐2‐enolide ( 2 ), and (5α,6β,12β,22R)‐5,6,12,21‐tetrahydroxy‐1‐oxowith‐24‐enolide( 3 ) on the basis of physicochemical evidence.     

Three New 24‐Nortriterpenoids from the Roots of Ilex asprella

Asprellols A–C ( 1 – 3 , resp.), three new 24‐nortriterpenoids, were isolated from the CHCl₃‐soluble fraction of 95% EtOH extract of the roots of Ilex asprella, together with a known nortriterpenoid. The structures of the new compounds were elucidated as 2,6β,20β‐trihydroxy‐3‐oxo‐11α,12α‐epoxy‐24‐norursa‐1,4‐dien‐28,13β‐olide ( 1 ), 2,6β‐dihydroxy‐3‐oxo‐11α,12α‐epoxy‐24‐norursa‐1,4,20(30)‐trien‐28,13β‐olide ( 2 ), and 2,6β‐dihydroxy‐3‐oxo‐11α,12α‐epoxy‐24‐noroleana‐1,4‐dien‐28,13β‐olide ( 3 ) on the basis of spectroscopic analyses.     

Dapholidins A – C,New Isomeric Biisoflavonoids From Daphne oleoides

Three new isomeric biisoflavonoids, dapholidins A–C ( 1 – 3 , resp.), have been isolated from the AcOEt‐soluble fraction of the MeOH‐soluble extract of the roots of Daphne oleoides, along with the known compounds daphwazirin ( 4 ), daphnetin 8‐O‐β‐D ‐glucopyranoside ( 5 ), daphnin ( 6 ), daphneticin 4″‐O‐β‐D ‐glucopyranoside ( 7 ), and 6,7‐dihydroxy‐3‐methoxy‐8‐[2‐oxo‐2H‐1‐benzopyran‐7‐(O‐β‐D ‐glucopyranosyl)‐8‐yl]‐2H‐1‐benzopyran‐2‐one ( 8 ). The structures of the new compounds were determined by spectroscopic analyses, including 1D‐ and 2D‐NMR.     

Flavonoids Isolated from Heat‐Processed Epimedium koreanum and Their Anti‐HIV‐1 Activities

Systematic phytochemical investigation on heat‐processed Epimedium koreanum led to the isolation of 13 flavonoids, including five new prenyl‐flavonol glycosides, koreanosides A–E ( 1 – 5 , resp.). Their structures were elucidated on the basis of detailed analysis of the 1D‐ and 2D‐NMR spectroscopic data and chemical reactions. Apigenin ( 11 ) exhibited moderate anti‐HIV‐1 activity with an EC₅₀ value of 12.8±3.27 μg/ml.     

Synthesis of Enantiomerically Pure 1,5,5‐Trideuterated cis‐ and trans‐2,4‐Dioxa‐3‐phosphadecalins. 31P‐NMR Evidence of Covalent‐Bond Formation and the Stereochemical Implications in the Course of the Inhibition of δ‐Chymotrypsin

The irreversible inhibition of δ‐chymotrypsin with the enantiomerically pure, P(3)‐axially and P(3)‐equatorially X‐substituted cis‐ and trans‐configurated 2,4‐dioxa‐3‐phospha(1,5,5‐²H₃)bicyclo[4.4.0]decane 3‐oxides (X=F, 2,4‐dinitrophenoxy) was monitored by ³¹P‐NMR spectroscopy. ¹H‐Correlated ³¹P{²H}‐NMR spectra enabled the direct observation of the vicinal coupling (³J) between the P‐atom of the inhibitor and the CH₂O moiety of Ser¹⁹⁵ (=‘Ser¹⁹⁵’(CH₂O)), thus establishing the covalent nature of the ‘Ser¹⁹⁵’(CH₂O? P) bond in the inhibited enzyme. The stereochemical course of the phosphorylation is dependent on the structure of the inhibitor, and neat inversion, both inversion and retention, as well as neat retention of the configuration at the P‐atom was found.     

Dimorphamides A – C,New Polyphenolic Amides from Atriplex dimorphostagia

Dimorphamides A–C ( 1 – 3 , resp.), three new polyphenolic amides, have been isolated from the BuOH‐soluble fraction of the whole plant of Atriplex dimorphostagia, along with two known compounds, thymidine and N‐[(E)‐feruloyl]tyramine. Their structures have been determined on the basis of spectral studies.     

Huangqiyenins G – J,Four New 9,10‐Secocycloartane (=9,19‐Cyclo‐9,10‐secolanostane) Triterpenoidal Saponins from Astragalus membranaceus Bunge Leaves

Four new 9,10‐secocycloartane (=9,19‐cyclo‐9,10‐secolanostane) triterpenoidal saponins, named huangqiyenins G–J ( 1 – 4 , resp.), were isolated from Astragalus membranaceus Bunge leaves. The acid hydrolysis of 1 – 4 with 1M aqueous HCl yielded D ‐glucose, which was identified by GC analysis after treatment with L ‐cysteine methyl ester hydrochloride. The structures of 1 – 4 were established by detailed spectroscopic analysis as (3β,6α,10α,16β,24E)‐3,6‐bis(acetyloxy)‐10,16‐dihydroxy‐12‐oxo‐9,19‐cyclo‐9,10‐secolanosta‐9(11),24‐dien‐26‐yl β‐D ‐glucopyranoside ( 1 ), (3β,6a,10α,24E)‐3,6‐bis(acetyloxy)‐10‐hydroxy‐12,16‐dioxo‐9,19‐cyclo‐9,10‐secolanosta‐9(11),24‐dien‐26‐yl β‐D ‐glucopyranoside ( 2 ), (3β,6α,9α,10α,16β,24E)‐3,6‐bis(acetyloxy)‐9,10,16‐trihydroxy‐9,19‐cyclo‐9,10‐secolanosta‐11,24‐dien‐26‐yl β‐D ‐glucopyranoside ( 3 ), and (3β,6α,10α,24E)‐3,6‐bis(acetyloxy)‐10‐hydroxy‐16‐oxo‐9,19‐cyclo‐9,10‐secolanosta‐9(11),24‐dien‐26‐yl β‐D ‐glucopyranoside ( 4 ).     

Clintoniosides A – C,New Polyhydroxylated Spirostanol Glycosides from the Rhizomes of Clintonia udensis

Phytochemical analyses were carried out on the rhizomes of Clintonia udensis (Liliaceae) with particular attention paid to the steroidal glycoside constituents, resulting in the isolation of three new polyhydroxylated spirostanol glycosides, named clintonioside A ( 1 ), B ( 2 ), and C ( 3 ). On the basis of their spectroscopic data, including 2D‐NMR spectroscopy, in combination with acetylation and hydrolytic cleavage, the structures of 1 – 3 were determined to be (1β,3β,23S,24S,25R)‐1,23,24‐trihydroxyspirost‐5‐en‐3‐yl O‐β‐D ‐glucopyranosyl‐(1→4)‐O‐[α‐L ‐rhamnopyranosyl‐(1→2)]‐β‐D ‐glucopyranoside ( 1 ), (1β,3β,23S,24S)‐3,21,23,24‐tetrahydroxyspirosta‐5,25(27)‐dien‐1‐yl O‐α‐L ‐rhamnopyranosyl‐(1→2)‐O‐[β‐D ‐xylopyranosyl‐(1→3)]‐β‐D ‐glucopyranoside ( 2 ), and (1β,3β,23S,24S)‐21‐(acetyloxy)‐24‐[(6‐deoxy‐β‐D ‐gulopyranosyl)oxy]‐3,23‐dihydroxyspirosta‐5,25(27)‐dien‐1‐yl O‐α‐L ‐rhamnopyranosyl‐(1→2)‐O‐[β‐D ‐xylopyranosyl‐(1→3)]‐β‐D ‐glucopyranoside ( 3 ).     

Artabotryols A – E,New Lanostane Triterpenes from the Seeds of Artabotrys odoratissimus

Six new lanostane triterpenes, artabotryols A, B, C1, C2, D, and E ( 1, 2, 3a, 3b, 4 , and 5 , resp.) have been isolated from the seeds of Artabotrys odoratissimus (Annonaceae). Their structures have been established as (3α,22S,25R)‐3‐hydroxy‐22,26‐epoxylanost‐8‐en‐26‐one ( 1 ), (3α,22S,25R)‐22,26‐epoxylanost‐8‐ene‐3,26‐diol ( 2 ), (3α,22S,25R,26R)‐26‐methoxy‐22,26‐epoxylanost‐8‐en‐3‐ol ( 3a ), (3α,22S,25R, 26S)‐26‐methoxy‐22,26‐epoxylanost‐8‐en‐3‐ol ( 3b ), (3α,22S,25R)‐3,22‐dihydroxylanost‐8‐en‐26‐oic acid ( 4 ) and (3α,7α,11α,22S,25R)‐3,7,11‐trihydroxy‐22,26‐epoxylanost‐8‐en‐26‐one ( 5 ) by spectroscopic studies and chemical correlations.     

Sesterterpenes and 2H‐Pyran‐2‐ones (=α‐Pyrones) from the Mangrove‐Derived Endophytic Fungus Fusarium proliferatum MA‐84

Two new tricyclic sesterterpenes, fusaprolifins A and B ( 1 and 2 ), and three new 2H‐pyran‐2‐one derivatives, prolipyrones A – C ( 3 – 5 ), were isolated and characterized from Fusarium proliferatum MA‐84, an endophytic fungus obtained from the fresh tissue of the marine mangrove plant Bruguiera sexangula. In addition, two known sesterterpenes, terpestacin ( 6 ) and fusaproliferin ( 7 ), and one known 2H‐pyran‐2‐one derivative, gibepyrone D ( 8 ), were also identified. The structures of these compounds were elucidated by detailed spectroscopic analyses. Fusaprolifin A ( 1 ) showed moderate activity against brine shrimp (Artemia salina), with a lethality rate of 49.5% at 100 μg/ml, while fusaprolifin B ( 2 ) showed weak activity.     

NMR‐Solution Structures and Affinities for the Human Somatostatin G‐Protein‐Coupled Receptors hsst1–5 of CF3 Derivatives of Sandostatin® (Octreotide)

The previously reported (Helv. Chim. Acta 2008 , 91, 2035) derivatives of octreotide ( 1 ) with a (CF₃)‐Trp substitution, i.e., 3 , and with open‐chain structures, i.e., 2, 4 , and 5 , have been tested for their affinities to hsst_1–5 receptors and subjected to a detailed NMR analysis. Their affinities vary from 15 nM to 5 μM , as compared to 0.6 nM to 0.8 μM for octreotide itself (Table 1). This decreased bioactivity may have had to be expected for the open‐chain compounds 4 and 5 ; possible reasons for this decrease in the case of CF₃ derivative of octreotide, 3 , are discussed. NMR Analysis (Tables 2 and 3) provides evidence for increased dynamics of all new derivatives 2 – 5 . The dynamics of the octreotide molecule 1 was analyzed by (natural‐abundance) longitudinal ¹³C‐T₁‐relaxation time measurements (Table 4), from which the conclusion is drawn that the backbone of the macrocycle is rather rigid on the time scale of this method.     

The ‘t‐Amino Effect’ of ortho‐Nitroso Amines. Synthesis of 2,6‐Diaminoadenine Derivatives from 6‐(Dialkylamino)‐5‐nitrosopyrimidines

The ‘t‐amino effect’ of amino‐nitroso compounds was documented by preparing the (dialkylamino)‐nitroso pyrimidines 4 – 18 , and cyclising them under thermal conditions in high yields to the purine derivatives 19 – 32 . The reactivity of the amino‐nitroso‐pyrimidines, particularly of 17 derived from diethyl iminodiacetate, and of 19 , derived from 1‐phenylimidazolidine, correlates with the stability of the intermediate azomethine ylide. Thermolysis of the amino‐nitroso‐pyrimidines 34 – 37 , possessing dialkylamino substituents at C(4) and C(6), proceeded by protiodenitrosation, leading to 38 – 41 .