Oligosaccharide Analogues of Polysaccharides Part 25

The ethynylated gluco‐azide 11 was prepared from the dianhydrogalactose 7 by ethynylation, transformation into the dianhydromannose 10 , and opening of the oxirane ring by azide (Scheme 1). The retentive alkynylating ring opening of 11 and of the corresponding amine 12 failed. (2‐Acetamidoglucopyranosyl)acetylenes were, therefore, prepared from the corresponding mannopyranosylacetylenes. Retentive alkynylating ring opening of the partially protected β‐D ‐mannopyranose 15 , possessing a C(3) OH group, gave a 85 : 15 mixture of 16 and the (E)‐enyne 17 . The alkyne 16 was deprotected to the tetrol 18 that was selectively protected and transformed into the C(2) O triflate 20 . Treatment with NaN₃ in DMF afforded a 85 : 15 mixture of the β‐D ‐gluco configured azide 21 and the elimination product 22 . Similarly, the α‐D ‐mannopyranosylacetylene 23 was transformed into the azide 26 . Retentive alkynylating ring opening of the ethynylated anhydromannose 28 gave the expected β‐D ‐mannopyranosyl 1,4‐dialkyne 29 as the main product besides the diol 28 , the triol 31 , and the (E)‐enyne 30 (Scheme 2). This enyne was also obtained from 31 by a stereoselective carboalumination promoted by the cis (axial) HO C(2) group. Deprotection of the dialkynylated mannoside 31 led to 32 , whereas selective silylation, triflation, and azidation gave a 3 : 7 mixture of the 1‐ethynylglucal 35 and the β‐D ‐gluco azide 36 , which was transformed into the diethynylated β‐D ‐GlcNAc analogue 38 . Similarly, the diethynylated α‐D ‐mannopyranoside 39 was transformed into the disilylated α‐D ‐GlcNAc analogue 41 , and further into the diol 42 and the monosilyl ether 43 (Scheme 5). Eglinton coupling of 41 gave the symmetric buta‐1,3‐diyne 44 , which did not undergo any further Eglinton coupling, even under forcing conditions. However, Eglinton coupling of the monosilyl ether 43 and subsequent desilylation gave the C₁‐symmetric cyclotrimer 45 in moderate yields.     

5‐Aza‐7‐deazaguanine DNA: Recognition and Strand Orientation of Oligonucleotides Incorporating Anomeric Imidazo[1,2‐a]‐1,3,5‐triazine Nucleosides

The base‐pairing properties of oligonucleotides containing the anomeric 5‐aza‐7‐deazaguanine 2′‐deoxyribonucleosides 1 and 5 are described. The oligonucleotides were prepared by solid‐phase synthesis, employing phosphoramidite or phosphonate chemistry. Stable `purine'⋅purine duplexes with antiparallel (aps) chain orientation are formed, when the α‐D ‐anomer 5 alternates with the β‐D ‐anomeric 2′‐deoxyguanosine ( 2 ) within the same oligonucleotide chain. Parallel (ps) oligonucleotide duplexes are observed, when the β‐D anomer 1 alternates with 2 . A renewed reversal of the chain orientation (ps→aps) occurs when compound 1 pairs with 2′‐deoxyisoguanosine ( 6 ). In all cases, it is unnecessary to change the orientation within a single strand when α‐D units alternate with their β‐D counterparts. Heterochiral base pairs of 5 (α‐D ) with 2′‐deoxyisoguanosine (β‐D ) are well accommodated in duplexes with random base composition and parallel chain orientation. Base pairs of 5 (α‐D ) with 2′‐deoxyguanosine (β‐D ) destabilize duplexes with antiparallel chains.     

Three New Cytotoxic ent‐Kaurane Diterpenoids from Isodon weisiensis C. Y. Wu

Three new cytotoxic ent‐kaurane diterpenoids, (1α,7α,14β)‐1,7,14‐trihydroxy‐ent‐kaur‐16‐en‐15,18‐dione ( 1 ), (1α,7α,14β)‐1,7,14,18,20‐pentahydroxy‐ent‐kaur‐16‐en‐15‐one ( 2 ), and (3β,7α,14β)‐3,7,14‐tris(acetyloxy)‐ent‐kaur‐16‐en‐15‐one ( 3 ), were isolated from Isodon weisiensis C. Y. Wu. Their structures were elucidated by spectroscopic methods, including 2D‐NMR techniques, and the crystal structure of 1 was determined by single‐crystal X‐ray‐diffraction analysis. The chosen crystal of 1 was orthorhombic, space group P2₁2₁2₁, and there were two molecules with little difference in bond length and bond angle in the least‐asymmetry unit. Compounds 1–3 showed significant cytotoxic activities against human‐cancer cell lines Bel‐7402 and HO‐8910.     

Synthesis of New Chlorin e6 Trimethyl and Protoporphyrin IX Dimethyl Ester Derivatives and Their Photophysical and Electrochemical Characterizations

In view of increasing demands for efficient photosensitizers for photodynamic therapy (PDT), we herein report the synthesis and photophysical characterizations of new chlorin e₆ trimethyl ester and protoporphyrin IX dimethyl ester dyads as free bases and Zn^II complexes. The synthesis of these molecules linked at the β‐pyrrolic positions to pyrano[3,2‐c]coumarin, pyrano[3,2‐c]quinolinone, and pyrano[3,2‐c]naphthoquinone moieties was performed by using the domino Knoevenagel hetero Diels–Alder reaction. The α‐methylenechromanes, α‐methylenequinoline, and ortho‐quinone methides were generated in situ from a Knoevenagel reaction of 4‐hydroxycoumarin, 4‐hydroxy‐6‐methylcoumarin, 4‐hydroxy‐N‐methylquinolinone, and 2‐hydroxy‐1,4‐naphthoquinone, respectively, with paraformaldehyde in dioxane. All the dyads as free bases and as Zn^II complexes were obtained in high yields. All new compounds were fully characterized by 1D and 2D NMR techniques, UV/Vis spectroscopy, and HRMS. Their photophysical properties were evaluated by measuring the fluorescence quantum yield, the singlet oxygen quantum yield by luminescence detection, and also the triplet lifetimes were correlated by flash photolysis and intersystem crossing (ISC) rates. The fluorescence lifetimes were measured by a time‐correlated single photon count (TCSPC) method, fluorescence decay associated spectra (FDAS), and anisotropy measurements. Magnetic circular dichroism (MCD) and circular dichroism (CD) spectra were recorded for one Zn^II complex in order to obtain information, respectively, on the electronic and conformational states, and interpretation of these spectra was enhanced by molecular orbital (MO) calculations. Electrochemical studies of the Zn^II complexes were also carried out to gain insights into their behavior for such applications.     

The 5‐Methylisocytosine β‐D‐Ribopyranosyl (4′ → 2′)‐Oligonucleotide

In the context of Eschenmoser's work on pyranosyl‐RNA (‘p‐RNA’), we investigated the synthesis and base‐pairing properties of the 5‐methylisocytidine derivative. The previously determined clear‐cut restrictions of base‐pairing modes of p‐RNA had led to the expectation that a 5‐methylisocytosine β‐D ‐ribopyranosyl (= D ‐pr(^MeisoC)) based (4′ → 2′)‐oligonucleotide would pair inter alia with D ‐pr(isoG) and L ‐pr(G) based oligonucleotides (D ‐pr and L ‐pr = pyranose form of D ‐ and L ‐ribose, resp.). Remarkably, we could not observe pairing with the D ‐pr(isoG) oligonucleotide but only with the L ‐pr(G) oligonucleotide. Our interpretation concludes that this – at first hand surprising – observation is caused by a change in the nucleosidic torsion angle specific for isoC.     

The Structure of a Novel Neutral Lipid A from the Lipopolysaccharide of Bradyrhizobium elkanii Containing Three Mannose Units in the Backbone

The chemical structure of the lipid A of the lipopolysaccharide (LPS) from Bradyrhizobium elkanii USDA 76 (a member of the group of slow‐growing rhizobia) has been established. It differed considerably from lipids A of other Gram‐negative bacteria, in that it completely lacks negatively charged groups (phosphate or uronic acid residues); the glucosamine (GlcpN) disaccharide backbone is replaced by one consisting of 2,3‐dideoxy‐2,3‐diamino‐D ‐glucopyranose (GlcpN3N) and it contains two long‐chain fatty acids, which is unusual among rhizobia. The GlcpN3N disaccharide was further substituted by three D ‐mannopyranose (D ‐Manp) residues, together forming a pentasaccharide. To establish the structural details of this molecule, 1D and 2D NMR spectroscopy, chemical composition analyses and high‐resolution mass spectrometry methods (electrospray ionisation Fourier‐transform ion cyclotron resonance mass spectrometry (ESI FT‐ICR MS) and tandem mass spectrometry (MS/MS)) were applied. By using 1D and 2D NMR spectroscopy experiments, it was confirmed that one D ‐Manp was linked to C‐1 of the reducing GlcpN3N and an α‐(1→6)‐linked D ‐Manp disaccharide was located at C‐4′ of the non‐reducing GlcpN3N (α‐linkage). Fatty acid analysis identified 12:0(3‐OH) and 14:0(3‐OH), which were amide‐linked to GlcpN3N. Other lipid A constituents were long (ω‐1)‐hydroxylated fatty acids with 26–33 carbon atoms, as well as their oxo forms (28:0(27‐oxo) and 30:0(29‐oxo)). The 28:0(27‐OH) was the most abundant acyl residue. As confirmed by high‐resolution mass spectrometry techniques, these long‐chain fatty acids created two acyloxyacyl residues with the 3‐hydroxy fatty acids. Thus, lipid A from B. elkanii comprised six acyl residues. It was also shown that one of the acyloxyacyl residues could be further acylated by 3‐hydroxybutyric acid (linked to the (ω‐1)‐hydroxy group).     

A New Coumarin and Carbazole Alkaloid from Clausena vestita D. D. Tao

Phytochemical investigation of the EtOH extract of Clausena vestita D. D. Tao led to the isolation of one new coumarin, clauslactone U ( 1 ), and one new carbazole alkaloid, clauszoline N ( 2 ), together with 28 known compounds. The structures of these compounds were established by using MS and 1D‐ and 2D‐NMR techniques, and by comparison with known analogues.     

Total Syntheses of Daphenylline,Daphnipaxianine A,and Himalenine D

We report the total syntheses of daphenylline ( 1 ), daphnipaxianine A ( 5 ), and himalenine D ( 6 ), three Daphniphyllum alkaloids from the calyciphylline A subfamily. A pentacyclic triketone was prepared by using atom‐transfer radical cyclization and the Lu [3+2] cycloaddition as key steps. Inspired by the proposed biosynthetic relationship between 1 and another calyciphylline A type alkaloid, we developed a ring‐expansion/aromatization/aldol cascade to construct the tetrasubstituted benzene moiety of 1 . The versatile triketone intermediate was also elaborated into 5 and 6 through a C=C bond migration/aldol cyclization approach.     

Total Syntheses of Daphenylline,Daphnipaxianine A,and Himalenine D

We report the total syntheses of daphenylline ( 1 ), daphnipaxianine A ( 5 ), and himalenine D ( 6 ), three Daphniphyllum alkaloids from the calyciphylline A subfamily. A pentacyclic triketone was prepared by using atom‐transfer radical cyclization and the Lu [3+2] cycloaddition as key steps. Inspired by the proposed biosynthetic relationship between 1 and another calyciphylline A type alkaloid, we developed a ring‐expansion/aromatization/aldol cascade to construct the tetrasubstituted benzene moiety of 1 . The versatile triketone intermediate was also elaborated into 5 and 6 through a C=C bond migration/aldol cyclization approach.     

Pentopyranosyl Oligonucleotide Systems. Communication No. 13

Among the members of a family of diastereoisomeric pentopyranosyl‐(4′→2′)‐oligonucleotide systems derived from D ‐ribose, D ‐xylose, L ‐lyxose, and L ‐arabinose, the α‐arabinopyranosyl system shows by far the strongest Watson? Crick base pairing. The system is, in fact, one of the strongest oligonucleotide‐type base‐pairing systems known. It undergoes efficient cross‐pairing with all the other members of the pentopyranosyl family, but not with RNA and DNA. The paper describes the synthesis and pairing of the properties of α‐L ‐arabinopyranosyl‐(4′→2′)‐oligonucleotides.     

Montecrinanes A–C: Triterpenes with an Unprecedented Rearranged Tetracyclic Skeleton from Celastrus vulcanicola. Insights into Triterpenoid Biosynthesis Based on DFT Calculations

Three new triterpenoids with an unprecedented 6/6/6/6‐fused tetracyclic carbon skeleton, montecrinanes A–C ( 1 – 3 ), were isolated from the root bark of Celastrus vulcanicola, along with known D:B‐friedobaccharanes ( 4 – 6 ), and lupane‐type triterpenes ( 7 – 12 ). The stereostructures of the new metabolites were elucidated based on spectroscopic (1D and 2D NMR) and spectrometric (HR‐EIMS and HR‐ESIMS) techniques. Their absolute configurations were determined by both NMR spectroscopy, with (R)‐(?)‐α‐methoxyphenylacetic acid as a chiral derivatizing agent, and biogenetic considerations. Biogenetic pathways for montecrinane and D:B‐friedobaccharane skeletons were proposed and studied by DFT methods. The theoretical results support the energetic feasibility of the putative biogenetic pathways, in which the 1,2‐methyl shift from the secondary baccharenyl cation represents a novel and key reaction step for a new montecrinane skeleton.     

Andhraxylocarpins A–E: Structurally Intriguing Limonoids from the True Mangroves Xylocarpus granatum and Xylocarpus moluccensis

Five new limonoids, including andhraxylocarpins A and B ( 1 and 2 ) which contain a 9‐oxa‐tricyclo[3.3.2.1^{7, 10}]undecane‐2‐ene motif, andhraxylocarpins C and D ( 3 and 4 ), which contain a (Z)‐bicyclo[5.2.1]dec‐3‐en‐8‐one substructure, and andhraxylocarpin E ( 5 ), which contains a tricyclo[3.3.1.1^{3, 6}]decane‐9‐one scaffold, were isolated from the seeds of two true mangroves, Xylocarpus granatum and Xylocarpus moluccensis, that were collected in the estuaries of Andhra Pradesh, India. The absolute configurations of these compounds were determined by extensive NMR investigations, single‐crystal X‐ray diffraction analysis, and by circular dichroism and optical rotatory dispersion spectroscopy, in combination with quantum‐chemical calculations. The pronounced structural diversity of limonoids from these mangroves might originate from environmental factors.     

A New 18(13 → 12β)‐abeo‐Lanostadiene Triterpenoid from Ganoderma fornicatum

A new triterpenoid, fornicatin C (= (3β)‐3‐hydroxy‐18(13 → 12β)‐abeo‐lanosta‐13(17),24‐dien‐18‐oic acid; 1 ), was isolated from the fruiting bodies of Ganoderma fornicatum, together with the known compounds fornicatin A ( 2 ) and fornicatin B ( 3 ), among other constituents. The structure of 1 was elucidated by means of spectroscopic techniques, and those of 2 and 3 were identified by comparing their spectroscopic data with those reported in the literature.     

Hypervalent Iodine in Synthesis. Part 86

N‐Arylation of uracil and its derivatives 2 with diaryliodonium salts 1 was investigated in order to explore a new synthetic methodology associated with N‐aryluracil derivatives. In the presence of K₂CO₃, the copper‐catalyzed arylation gave N¹,N³‐diarylation products with high selectivity and in good yields (Table 2). However, the use of NaOAc as the base in the copper‐catalyzed arylation of 6‐methyluracil ( 2a ) resulted in N³‐arylation products with high selectivity, and, in the copper‐catalyzed arylation of uracil ( 2b ) or 5‐methyluracil (=thymine; 2c ), N¹‐arylation products were the major products (Table 3).     

10‐Step Asymmetric Total Synthesis and Stereochemical Elucidation of (+)‐Dragmacidin D

The asymmetric synthesis of dragmacidin D ( 1 ) was completed in 10 steps. Its sole stereocenter was set by using direct asymmetric alkylation enabled by a C₂‐symmetric tetramine and lithium N‐(trimethylsilyl)‐tert‐butylamide as the enolization reagent. A central Larock indole synthesis was employed in a convergent assembly of the heterocyclic subunits. The stereochemical evidence from this work strongly supports the predicted S configuration at the 6′′′ position, which is consistent with other members of the dragmacidin family of natural products.     

Divergent Biomimetic Total Syntheses of Ganocins A–C,Ganocochlearins C and D,and Cochlearol T

A divergent synthetic approach to six Ganoderma meroterpenoids, namely ganocins A–C, ganocochlearins C and D, and cochlearol T, has been developed for the first time. This synthetic route features a two‐phase strategy which includes early‐stage rapid construction of a common planar tricyclic intermediate followed by highly selective late‐stage transformations into various Ganoderma meroterpenoids. Key to the strategy are a bioinspired intramolecular hetero‐Diels–Alder reaction and Stahl‐type oxidative aromatization, allowing efficient formation of the common tricyclic phenol intermediate. A nucleophilic dearomatization of the phenol unit, combined with a regioselective 1,4‐reduction of the resulting dienone, enabled rapid access to ganocins B and C. Additionally, site‐selective Mukaiyama hydration, followed by an intramolecular oxa‐Michael addition/triflation cascade, served as a key strategic element in the chemical synthesis of ganocin A.     

Enantioselective Total Synthesis of (+)‐Plumisclerin A

The first and enantioselective total synthesis of (+)‐plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring‐formation protocol was adopted to generate the characteristic tricycle[4.3.1.0^1,5]decane and trans‐fused dihyrdopyran moiety. Scalable enantioselective La^III‐catalyzed Michael reaction, palladium(0)‐catalyzed carbonylation and SmI₂‐mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D‐ring system having six continuous stereogenic centers and two all‐carbon quaternary centers. The trans‐fused dihyrdopyran moiety with an exo side‐chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)‐plumisclerin A.     

Functionalised Monocyclic Five‐ to Seven‐Membered exo‐Glycals by Alkynol Cycloisomerisation of Hydroxy Buta‐1,3‐diynes and 1‐Haloalkynols

Base‐promoted (KOH or MeONa in MeOH, or NaH in THF) cycloisomerisation of partially benzylated, 1‐substituted (R = Ph CC, pyridin‐2‐yl, or Br) ald‐1‐ynitols leads to (Z)‐configured five‐, six‐, and seven‐membered exo‐glycals. The reactivity of the ald‐1‐ynitols depends upon their configuration. The ald‐1‐ynitols were derived from 2,3,5‐tri‐O‐benzyl‐D ‐ribofuranose 1 , and the corresponding, partially O‐benzylated galactose, glucose, and mannose hemiacetals by ethynylation. The hex‐1‐ynitol 2 derived from 1 (61%) was transformed via the 1‐phenylbuta‐1,3‐diyne 3 and the 1‐(pyridin‐2‐yl)acetylene 5 into the five‐membered exo‐glycals 4 and 6 (in 66 and 72% yields, resp., from 2 ). The analoguous ethynylation of 2,3,4,6‐tetra‐O‐benzyl‐D ‐galactose 8 was accompanied by elimination of one benzyloxy (BnO) group to the hept‐3‐en‐1‐ynitol 9 (71%), which was transformed into the non‐5‐ene‐1,3‐diynitol 10 and further into the six‐membered exo‐glycal 11 (50% from 9 ). Addition of Me₃SiCCH to the galactose 8 and to the gluco‐ and manno‐analogues 16 and 24 gave epimeric mixtures of the silylated oct‐1‐ynitols (86% of 12L / 12D 45 : 55, 94% of 17L / 17D 7 : 3, and 86% of 25L / 25D 55 : 45), which were separated by flash chromatography, and individually transformed into the corresponding 1‐bromooct‐1‐ynitols. Upon treatment with NaH in THF, only the minor epimers 13L, 18D , and 26D cyclised readily to form the seven‐membered hydroxy exo‐glycals. They were acetylated to the more stable monoacetates 14L, 23D , and 28D (82–89% overall yield). Under the same conditions, the epimers 13D, 18L , and 26L decomposed within 12 h mostly to polar products. The difference of reactivity was rationalised by analysing the consequences of an intramolecular C(3)O H ⋅⋅⋅ ⁻OC(7) H‐bond of the intermediate alkoxides on the orientation of ⁻O C(7) of 13L, 18D , and 26D and its proximity to the ethynyl group.     

Syntheses of β‐C(1→3)‐Glucopyranosides of 2‐ and 4‐Deoxy‐D‐hexoses

The Oshima? Nozaki (Et₂AlI) condensation of isolevoglucosenone ( 4 ) with 2,6‐anhydro‐3,4,5,7‐tetra‐O‐benzyl‐D ‐glycero‐D ‐gulo‐heptose ( 5 ) gave an enone 6 that was converted with high stereoselectivity to 3‐C‐[(1R)‐2,6‐anhydro‐D ‐glycero‐D ‐gulo‐heptitol‐1‐C‐yl]‐2,3‐dideoxy‐D ‐arabino‐hexose ( 1 ; 1 : 1 mixture of α‐ and β‐D ‐pyranose), and to 3‐C‐[(1R)‐2,6‐anhydro‐D ‐glycero‐D ‐gulo‐heptitol‐1‐C‐yl]‐2,3‐dideoxy‐D ‐lyxo‐hexose ( 2 ; 2.7 : 1.4 : 1.0 : 1.4 mixture of α‐D ‐furanose, β‐D ‐furanose, α‐D ‐pyranose, and β‐D ‐pyranose). The Oshima? Nozaki (Et₂AlI) condensation of levoglucosenone ( 17 ) with aldehyde 5 gave an enone 18 that was converted with high stereoselectivity to 3‐C‐[(1R)‐2,6‐anhydro‐D ‐glycero‐D ‐gulo‐heptitol‐1‐C‐yl]‐3,4‐dideoxy‐α‐D ‐arabino‐hexopyranose ( 3 ; single anomer).     

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.