Diastereoselective concise syntheses of the polyhydroxylated alkaloids DMDP and DAB

A diastereoselective concise synthesis of the iminosugars DMDP and DAB is presented starting from l-xylose and affording the two alkaloids in good yields of 35% and 22% over seven and eight steps, respectively. The Petasis borono–Mannich reaction of 3,5-di-O-benzyl-l-xylofuranose with benzylamine and (E)-styrylboronic acid served as the nitrogen-introducing key step furnishing the new C–N bond in an entirely diastereoselective manner. A chemo- and regioselective O-mesylation followed by an intramolecular S_N2-cyclisation allowed the formation of the pyrrolidine ring. Ozonolysis of the styryl double bond and subsequent reduction to form the C-5 hydroxymethyl substituent followed by hydrogenolysis of the benzyl protecting groups concluded the DMDP synthesis. Furthermore, an unexpected fragmentation process during the ozonolysis reaction also gave access to the C-5 decarbinolated DMDP derivative DAB.     

Synthesis of a new class of bisheterocycles via the Heck reaction of eudesmane type methylene lactones with 8-bromoxanthines

The eudesmane-type methylene lactones (isoalantolactone, alantolactone, 4,15-epoxyisoalantolactone, 2′,2′-dichloro-4H-spiro[cyclopropane-1′,4-eudesma-11(13)-en-8β,12-olide], and alantolactone) react with 8-bromoxanthines (8-bromocaffeine, 8-bromotheobromine, 8-bromo-3-butyltheobromine, 8-bromotheophylline, 8-bromo-9-butyltheophylline) under Heck reaction conditions to produce the target (E)-13-(2,6-dioxo-2,3-dihydro-1H-purin-8-yl)eudesma-4(15),11(13)-dien-8β,12-olides and the subsequent endocyclic isomers - 11-(2,6-dioxo-2,3-dihydro-1H-purin-8-yl)-13-normethyleudecma-4(15)-7(11)-dien-8α,12-olides. It was revealed that the yield and product ratio depends on the reaction conditions and the structure of methylene lactone. The effectiveness of Pd(OAc)₂–caffeine catalytic system has been demonstrated in this reaction. The electric eel acetylcholinesterase inhibitory activity of the eudecmanolide-xanthine hybrids was evaluated. Among the new type bisheterocycles compound 27 with butyl and 2-oxodecahydronaphtho[2,3-b]furan-3(2H)-ylidene)methyl substituents at C-7 and C-8 of the xanthine core showed moderate activity with IC₅₀ value of 40 μM.     

Enantioselectivities of yeast epoxide hydrolases for 1,2-epoxides

Kinetic resolution of homologous series of unbranched 1,2-epoxyalkanes (C-4 to C-12), 1,2-epoxyalkenes (C-4, C-6 and C-8), a 2,2-dialkylsubstituted epoxide (2-methyl-1,2-epoxyheptane) and a benzyloxy-substituted epoxide (benzyl glycidyl ether) was investigated using resting cells of 10 different yeast strains. Biocatalysts with excellent enantioselectivity (E>100) and high initial reaction rates (>300 nmol/min/mg dry weight) were found for the 2-monosubstituted aliphatic epoxides C-6 to C-8. Yeast strains belonging to the genera Rhodotorula, Rhodosporidium and Trichosporon all preferentially hydrolyzed (R)-1,2-epoxides with retention of configuration. The epoxide hydrolases of all the yeast strains are membrane-associated.     

Synthesis and evaluation of 1-deoxy-8-epi-castanospermine, 1-deoxy-8-hydroxymethyl castanospermine, and (6S,7S,8R,8aR)-8-amino-octahydroindolizine-6,7-diol

A short, versatile, and enantioselective synthesis of 1-deoxy-8-epi-castanospermine (5), 1-deoxy-8-hydroxymethyl castanospermine (6), and (6S,7S,8R,8aR)-8-amino-octahydroindolizine-6,7-diol (7) is achieved from a common template 12. The key step utilized is PET provoked amine radical cyclization of 11 to 12 in excellent diastereoselectivity. The exocyclic double bond at C-8 of the template is functionalized to obtain 5-7 as exclusive diastereomers. 1-Deoxy-8-epi-castanospermine exhibited inhibition of α- and β-galactosidase and β-glucosidase. Compounds 6 and 7 were found to be weak inhibitors of β-glucosidase.     

A Flexible Approach to Azasugars: Asymmetric Total Syntheses of (+)‐Castanospermine, (+)‐7‐Deoxy‐6‐epi‐castanospermine,and (+)‐1‐epi‐Castanospermine

The asymmetric total synthesis of natural azasugars (+)‐castanospermine, (+)‐7‐deoxy‐6‐epi‐castanospermine, and synthetic (+)‐1‐epi‐castanospermine has been accomplished in nine to ten steps from a common chiral building block (S)‐ 8 . The method features a powerful chiral relay strategy consisting of a highly diastereoselective vinylogous Mukaiyama‐type reaction with either chiral or achiral aldehydes (≥95 % de; de=diastereomeric excess) and a diastereodivergent reduction of tetramic acids, which allows formation of three continuous stereogenic centers with high diastereoselectivities. The method also provides a flexible access to structural arrays of 5‐(α‐hydroxyalkyl)tetramic acids, such as 17/34 , and 5‐(α‐hydroxyalkyl)‐4‐hydroxyl‐2‐pyrrolidinones, such as 18 and 25/35 a . The method constitutes the first realization of the challenging chiral synthons A and D and thus of the conceptually attractive retrosynthetic analysis shown in Scheme 1 in a highly enantioselective manner.     

Synthesis of C1- and C8a-epimers of (+)-castanospermine from d-glucose derived γ,δ-epoxyazide: intramolecular 5-endo epoxide opening approach

A concise synthesis of two diastereomers of (+)-castanospermine namely 1- and 8a-epi-castanospermine 1b and 1c, respectively, is reported from d-glucose. The methodology involves stereoselective cross metathesis of d-glucose derived alkene 2 with 4-bromo-1-butene followed by azide displacement and m-CPBA oxidation to afford diastereomeric γ,δ-epoxyazides 5a/5b. The Staudinger reaction of epoxyazide 5a followed by reaction with benzylchloroformate (CbzCl) unexpectedly furnished 1,3-oxazinan-2-one derivative 7 whose stereochemistry was establish by single crystal X-ray. This helps to assign the stereochemistry in the epoxidation reaction. The reduction of 5a/5b was then carried out by transfer hydrogenation to provide γ,δ-epoxyamine that concomitantly undergoes intramolecular 5-endo-tet cyclization to afford hydroxypyrrolidine ring skeleton with sugar framework-a precursor to castanospermine analogues 1b/1c.     

Enantiospecific synthesis of ABC-ring system of A-nor and abeo 4(3→2) tetra and pentacyclic triterpenes

Enantiospecific synthesis of ABC-ring systems of A-nor and abeo 4(3→2) tetra and pentacyclic triterpenes has been accomplished starting from the readily available monoterpene (R)-carvone. (R)-Carvone was used as the B-ring of the target molecules. A lithium-liquid ammonia mediated cyclisation of δ,?-unsaturated ester was employed for the cyclopentannulation at the C-5 and C-6 carbons of carvone and an RCM reaction was employed for the cyclohexannulation to generate the ABC-ring system of A-nor tetra and pentacyclic triterpenes. The strategy has been extended for the synthesis of the ABC-ring system of abeo 4(3→2) tetra and pentacyclic triterpenes.     

Total synthesis of malyngamide X and its 7′S-epi isomer

Stereoselective syntheses of malyngamide X (1) and its 7′(S)-epimer are described. A Lewis acid (Et₂AlCl) mediated anti-aldol reaction was employed to generate the stereocenters C-7 and C-8. The route is convergent and provides a convenient access to the synthesis of structural variants of malyngamide X. Stereochemistry at C-7′ in the molecules of natural and synthetic 1, and 7′(S)-epi1 was confirmed by NMR chiral solvation experiments.     

Solid-phase synthesis of 2,6- and 2,7-diamino-4(3H)-quinazolinones via palladium-catalyzed amination

A new procedure for the solid-phase synthesis of 2,6- and 2,7-diamino-4(3H)-quinazolinones is described. The method involves coupling of 2,4,6- and 2,4,7-trichloroquinazoline to a solid support via benzyl alcohol type linkers, subsequent displacement of chlorine at C-2 then at the C-6 or C-7 positions by amines (Fig. 1) and the cleavage of the products from the resin. The palladium-catalyzed amination of C-6 and C-7 positions with a representative set of amines in the presence of 2-(di-t-butylphosphino)biphenyl (DTBPBP), P(t-Bu)₃ and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) ligands has been investigated. This method should prove to be a useful tool for constructing combinatorial libraries containing the 4(3H)-quinazolinone moiety.     

Synthèse d'analogues de dérivés dioxaprostanoïques à partir du d et du l-xylose

Epoxides 7, 8 and 9 have been prepared from d and l-xylose, and used for the synthesis of a precursor of ent-(11-oxa)PG 19 and of 9,13-and 7,11-dioxaprostanoïc acids 28 and 31. The site of the opening of the epoxidcs 7 and 9 with the carbanion derived from bis-(phenylth)romethane and with LiAlH₄ is shown by establishing structures of the products 11, 12, 20 et 21 by ¹³CNMR spectroscopy.     

Studies on oxidation of ergot alkaloids: oxidation and desaturation of dihydrolysergol—stereochemical requirements

A new method for the oxidation of ergoline alcohols to aldehydes was found (TFFA-DMSO, −78 °C, then DIPEA). Structural features of ergolines required for successful C7-C8 double bond introduction via Polonovski-Potier reaction of respective 6-N-oxides were defined and experimentally confirmed: (i) the presence of electron-withdrawing group at C-8; (ii) trans-diaxial orientation of N6-O and C7-H bonds (both requirements are fulfilled for dihydrolyserg-17-al and its 2,4-dinitrophenyl hydrazone prepared in this work).     

Addition conjuguée dans le thf-hmpt d'arylacétonitriles lithies aux cyclohexèn-2 ones substituées: intervention des facteurs stériques et électroniques

The reaction of lithiated arylacetonitriles 2a-c with 2-cyclohexenones 3-9 in THF-HMPA (80:20 v/v) at ?70° leads in all cases but one to δ-ketoalkylnitriles, resulting from 1,4-addition. The only case where some 1,2-addition takes place is the reaction of 2a with 4,4-dimethyl 2-cyclohexenone 7. The formation of allylic alcoholates, products of 1,2-addition, is shown to be reversible in this solvent mixture. However, in several cases, kinetic control of 1,4-addition is demonstrated. The rate of formation of 1,4-addition products depends upon the arylacetonitrile substituents: 2a >2b >2c (i.e. the higher lying the nucleophile HOMO the faster the reaction). It is also sensitive to the cyclohexenone substituents; although methyl on C-2 and gem-dimethyl on C-5 or t-butyl on C-4 have small influence on the reaction rate, methyl on C-3 or gem dimethyl on C-4 induce a noticeable rate decrease. The addition, of 2b on 4-t-butyl 2-cyclohexenone 8 leads, at the early stage, to a predominating isomer 15b, to which the trans diaxial configuration of the substituents has been attributed by 250 MHz ¹H NMR. A single transition state model, reagent-like, where the nucleophile approaches the C-C bond by the less hindered face of the 2-cyclohexenone in a 1,2-diplanar conformation, the CN substituent being directed towards the C=0 group, accounts for all the substituent effects and the stereoselectivity observed.     

Total synthesis of the alkaloid (−)-codonopsinine from l-xylose

The enantiopure total synthesis of (−)-codonopsinine is described from commercially available l-xylose in 20% overall yield. The key steps included Julia trans olefination and cascade epoxidation-cyclisation strategies.     

An olefin metathesis route for the preparation of (1-->6)-linked C-disaccharide glycals. A convergent and flexible approach to C-saccharide synthesis

A convergent route to a variety of C-1-disaccharide glycals based on the olefin metathesis reaction of enol ethers and alkenes is described. The DCC-mediated coupling reaction of a variety of pentose enitols (1a-c) with a number of C-5- and C-6-monosaccharide carboxylic acids (2a-e) gave the corresponding esters 3a-l in good yield. Methylenation of these compounds was followed by ring-closing metathesis, mediated by the Schrock molybdenum catalyst 8 in warm toluene, to provide the target C-disaccharide glycals 5a-l. The formed enol ether double bond in 5a was then transformed, via standard manipulations, into a variety of C-disaccharide derivatives 21-25.     

4,5-erythro/5,6-threo-Stereoselectivity in vinylogous Mukaiyama aldol addition of a silyloxypyrrole to a threose derivative: stereochemical rationalization and relevance to (+)-castanospermine synthesis

Vinylogous Mukaiyama aldol addition of N-p-methoxybenzyl-4-methoxy-2-trimethylsilyloxypyrrole 7 to bis-MOM threose 6 using SnCl₄ as promoter gave the 4,5-erythro/5,6-threo adduct 8, with the correct absolute configurations for the castanospermine framework as determined by a single-crystal X-ray structure. A transition-state model is presented to rationalize the stereoselectivity.     

A practical one-pot radical-ionic sequence for the preparation of epoxides: application to the synthesis of unnatural polyhydroxylated alkaloids

An efficient one-pot sequence for the preparation of epoxides from α-iodoesters or α-iodonitriles and allylic alcohols is described. This sequence is based on the use of iodine atom transfer reaction onto allylic alcohols followed by a ring closing epoxidation reaction of the halohydrin intermediates. The feasibility of this sequence is showcased in the synthesis of the perhydroaza-azulene, an unnatural analog of castanospermine.     

Synthesis of poinsettifolin A

A synthesis of poinsettifolin A (1), a prenylated flavonol isolated from Dorstenia poinsettifolia, is described. Two routes starting from quercetin were explored, and 1 could be prepared if a prenyl group first was incorporated at C-6 of the protected quercetin followed by a condensation with citral at C-8. The key synthetic steps are a Mitsunobu reaction, an europium (III)-catalysed Claisen rearrangement coupled with cross-metathesis, and a benzopyran-forming geranylation. The two geranylated 3,5,3′,4′-tetrahydroxyflavonols prepared, 1 and 3, were assayed for antileishmanial activity against Leishmania amazonensis and Leishmania braziliensis, and found to be active. Compound 3 showed cytotoxic activity against leukaemia and lung cancer cells while 1 lacked cytotoxicity.     

Efficient synthesis and cytotoxicity of novel microtubule-stabilizing agent ceratamine A analogues

An efficient synthesis of microtubule-stabilizing agent ceratamine A analogues is described. The key step is the application of either reductive Heck reaction or Heck reaction to construct the imidazo[4,5-d]azepine core. Thirteen novel analogues of ceratamine A were synthesized and evaluated for their in vitro cytotoxicity against five human cancer cell lines (HCT-116, HepG2, BGC-823, A549 and A2780). It was the first report about the systematic structural modification and SARs study of ceratamine A. The results demonstrated that bulky substituents at C-14 and C-16 could enhance the cytotoxicy and modification at N-7 was crucial for high potency. Especially compound 1f bearing methyl group at C-14 and C-16, and compound 1k bearing benzyl group on N-7, showed better cytotoxicy than ceratamine A against A549.     

Total syntheses of both enantiomers of amphirionin 4: A chemoenzymatic based strategy for functionalized tetrahydrofurans

The total syntheses of (?)-amphirionin-4 and (+)-amphirionin-4 have been achieved in a convergent and enantioselective manner. The tetrahydrofuranol cores of amphirionin-4 were constructed in optically active form by enzymatic resolution of racemic cis-3-hydroxy-5-methyldihydrofuran-2(3H)-one. The polyene side chain was efficiently synthesized using Stille coupling. The remote C8-stereocenter was constructed using the Nozaki-Hiyama-Kishi coupling reaction. Detailed ¹H NMR studies of Mosher esters of (?)-amphirionin-4 and (+)-amphirionin-4 were carried out to support the assignment of the absolute configurations of the C-4 and C-8 asymmetric centers of amphirionin-4.     

One-pot synthesis,spectroscopic characterization and DFT study of novel 8-azacoumarin derivatives as eco-friendly insecticidal agents

A series of sixteen 8-azacoumarin derivatives bearing aryl moieties at C-5 and C-7 was designed and synthesized by a concise and facile procedure utilizing grinding and ultrasound approaches. The efficient multi-component protocols proceeded smoothly and in the absence of solvent to furnish the target products in moderate to good yields. All the synthesized molecules were characterized via ¹HNMR, ¹³CNMR, IR, mass spectra, and elemental analyses. The density functional theory (DFT) was then used to discover the structural and electronic characteristics of such compounds. Finally, an insecticidal study against Plutella xylostella and Helicoverpa armigera on the synthesized compounds is reported. The bioassay results indicated that some of the tested compounds showed potency ranging from good to moderate. In particular, analogs 6i and 6l, among the tested compounds, showed even more potency than commercial chlorpyrifos. On the other hand, the rest of the tested compounds showed moderate to weak activities.