A concise synthesis of harzialactone A from d-glucose and revision of absolute stereochemistry

Synthesis of 2 by a chiron approach is described starting from monoacetone-d-glucose 4. Absolute stereochemistry of natural harzialactone A 1 (2S,4S) is revised to 2 (2R,4R).     

Synthesis and in vitro activity of a non-epimerizable analog of the angiotensin-converting enzyme inhibitor A58365A

The 3-methyl-substituted analog (±)-3 of the angiotensin converting enzyme inhibitor A58365A (1) was synthesized from lactone 4 and amino acid ester 16, via key intermediates 18, 19 and 21a,b. Compound (±)-3 was found to possess powerful ACE inhibitory activity (IC₅₀ = ca 500 nM), as judged by in vitro tests against porcine kidney ACE, under conditions in which the commercial drug captopril has IC₅₀ = 280 nM.     

A case of non-electroselective and-π-facial non-stereoselective addition to norbornadiene

2-(4-chlorophenylimino)-1-phenylethanone 5 or its adduct 6 with methanol add to norbornadiene 1 under BF₃, or SO₂ catalysis with low degree of electroselectivity and π-facial stereoselectivity giving 7, 8, 9, and 10. A reaction mechanism is proposed.     

A new total synthesis of (±)-oestrone

A conceptually new total synthesis of oestrone, based on a novel cascade of radical cyclisations from the iodo aryl vinylcyclopropane 2, via 10, 15, 16 and 17, leading to the intermediate trans,anti,trans-oestradiol derivative 11 in one step, is described. Oxidation of 11, followed by demethylation of the resulting aryl methyl ether 18 then gives (±)-oestrone 1.     

A synthesis of a common intermediate to the lactone-pyrrolidinone ring systems in oxazolomycin A and neooxazolomycin

A 5-exo-dig radical cyclisation of the bromoamide 34 derived from the enantiopure α-ethynyl substituted amino alcohol 31 led to a 2:1 mixture of β-C3 and α-C3 methyl epimers of the pyrrolidinone 35a-36a in a combined yield of 73%. Treatment of the homoallylic alcohol 35b, derived from 35a, with OsO₄-TMEDA, gave a single diastereoisomer of the pyrrolidinone triol 37, resulting from selective dihydroxylation from the β-face, i.e. syn to the CH₂OH group of 35b. The pyrrolidinone triol 37 is a potential common precursor, cf. 9, to the spiro β-lactone pyrrolidinone 8 and the γ-lactone pyrrolidinone 10 ring systems in oxazolomycin A (1) and neooxazolomycin 2, respectively. Sequential protection of the 1,2-diol functionality in 37 as the acetonide 39, and the primary alcohol group in 39 as the SEM ether 41a, followed by methylation of the nitrogen centre in 41a, using NaH-MeI, then gave the selectively protected pyrrolidinone 42.     

A simple synthesis of cytotoxic endoperoxide lactones

A series of dihydrobenzofuran-2-one 3 have been submitted to various dienophiles: whereas maleic anhydride led only to the adducts 4a,b, singlet oxygen gave the expected new endoperoxide lactones 5a-d, 6 and 7a,b, three of them showing interesting cytotoxicity towards various cancer cell lines.     

A synthesis of (−)hibaene

A total synthesis of (?)hibaene 1 is described. The key steps are a photochemical cycloaddition of vinyl acetate on the α-β unsaturated ketone 2 and a Wagner-Meerwein type rearrangement of the diols 14 and 15, which contain a highly strained cyclobutane ring. A selective esterification of the rearranged diols 22a or 22b leads to intermediates which can conveniently be transformed into (?)hibaene.     

Dysotriflorins A–M,triterpenoids from Dysoxylum densiflorum

Thirteen new triterpenoids, dysotriflorins A–M (1–13), were isolated from Dysoxylum densiflorum barks, and their structures were elucidated on the basis of NMR spectroscopic data and X-ray crystallography. Dysotriflorins A, B, and K–M (1, 2, and 11–13) were concluded to be unique 13,17-secodammarane triterpenoids, and dysotriflorins C–J (3–10) to be dammarane triterpenoids. Dysotriflorins showed in vitro cytotoxic activity against several cancer cell lines.     

Phosgenation of benzyltetrahydroisoquinolines: A new method of berbines and berbin-8-ones synthesis

A novel synthesis of the berbine ring skeleton by the way of the berbin-8-ones is reported. Treatment of 1-benzyl-1,2,3,4-tetrahydroisoquinolines 1a-d with phosgene gas gave a new series of N-chloroformyl derivatives 2a-d. Intramolecular ring closure of these compounds in presence of a Lewis acid catalyst afforded berbin-8-ones 3a-d in good yield. The choice of the cyclization catalyst is discussed. Reduction of products 3a-d with lithium aluminium hydride gave the berbines 4a-d. Hydrolysis of berbines 4b,c gave the new 3-hydroxyberbines 4e,f. Preparation of new starting benzyltetrahydroisoquinolines 1b,c are described.     

Synthesis of lipid A analogues containing glucose instead of glucosamine and their LPS-antagonistic activities

Lipid A analogues containing glucose in substitution for glucosamine on the reducing end were synthesized, and the inhibitory activities on LPS-induced TNFα production (LPS-antagonistic activity) in vitro using human whole blood cells were measured. The IC₅₀ values (nM) of these ten compounds, 8, 14, 21, 31, 40, 51, 57, 62, 67 and 72, were 11.2, 15.4, 2.7, 0.1, 0.4, 1.3, 3.2, 3.2, 1.4 and 14.4, respectively. And also inhibitory activities (ID₅₀) on TNFα production toward galactosamine loaded C3H/HeN mice in vivo of compounds 21, 31, 57, 62 and 67 were measured. The values of these compounds were 0.29, 0.50, 0.61, not dose-dependent and 0.33 mg/kg, respectively.     

A radical version of the bromine cyclization of alkenols

The scope of an alkoxyl radical version of the classical bromine cyclization was explored. Oxygen-centered radicals were generated in photochemically initiated radical chain reactions from N-alkenoxy-4-(p-chlorophenyl)thiazole-2(3H)-thiones 5a–c, N-alkenoxy-4-methylthiazole-2(3H)-thiones 13, 14, 21, rac-23, and N-alkenoxypyridine-2(1H)-thiones 6d–f, 16, rac-25. Thus, 2-(2-bromopropyl)-substituted tetrahydrofurans 4a–c, which are minor compounds (< 10 %) in NBS-mediated bromine cyclizations of corresponding alkenols 1a–c, were prepared in 87–90 % yield and with good to excellent diastereoselectivities. Further, photochemical conversions of O-alkyl thiohydroxamates 14, 16 and 21 in benzene and BrCCl₃ afforded β-oxy-functionalized bromomethyl substituted tetrahydrofurans 29, 34, and 36. The results of this study indicate, that efficient 5-exo-trig cyclizations of β-oxy-substituted 4-penten-1-oxyl radical require an electronwithdrawing substituent at the β-heteroatom substituent. In the third part of the study a synthetically useful new access to oxabicyclo〚4.3.0〛nonanes rac-38 and rac-40 is reported which takes profit from highly diastereoselective 5-exo-trig-ring closures and, in case of the formation of rac-40, stereoselective bromine atom transfer.     

Absolute configurations of griseorhodins A and C

The known antibiotic and cytotoxic compounds griseorhodin A (1) and griseorhodin C (2) were produced in solid culture by Streptomyces puniceus AB10, which was isolated from the leaf-cutter ant Acromyrmex rugosus rugosus. Their absolute configurations were unambiguously established as 6S,6aR,7S,8S and 6R,6aR,7S,8R, respectively, using vibrational circular dichroism (VCD) and density functional theory (DFT) calculations.     

The dioxanone-to-dihydropyran Claisen rearrangement. Synthesis of C(7)-C(13) fragments of erythronolides A and B

Iterative applications of the dioxanone-to-dihydropyran Claisen rearrangement have resulted in the efficient conversion of (S)-(−)-ethyl lactate to the erythronolide A and B C(7)C(13) subunits 19, 23, and 27 via the common synthetic intermediates 13 and 22.     

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.     

Approaches to the synthesis of arisugacin A

Approaches to the synthesis of the important acetylcholinesterase inhibitor, arisugacin A, are described. Two different routes to the key AB ring system are described: the first utilizes an intramolecular Diels-Alder reaction on a furan substrate and the second a 6π-electrocyclization of a substituted triene followed by cycloaddition with singlet oxygen. The successful synthesis of a fully functionalized AB ring system of arisugacin A, the tetraol 52 from hydroxy-β-ionone 22 in 16 steps and 9.3% overall yield is described. Several useful synthetic transformations to this molecule and its analogues are reported, e.g., the formation of the furan Diels-Alder cycloadduct 14 and its conversion into the oxa-bridged structures 17 and 21, the preparation of the dienes 25 and 26 and the conversion of the later into the endoperoxide 30 and its diol 36, the preparation of the endoperoxide 40 and the oxa-bridged system 42, and finally the use of the enelactone 43 and its ultimately successful conversion into 52. In addition, several novel rearrangements are described, producing the unusual compounds 62, 65, and 67. Finally, the successful coupling of the pyrone unit to the AB ring system is described to give compounds 70 and 71. The novel reduction of these compounds to the cyclic ether 74 is described.     

Ceratoluteolin: A new flavonoid from Salvia ceratophylla from Jordan

Ceratoluteolin 1, a new luteolin derivative was isolated from Salvia Ceratophylla growing wild in Jordan along with other 14 known compounds including two sterols, two triterpenes, four flavonoids and six phenolic compounds, one of which is reported for the first time from Lamiaceae family. The isolated compounds were genkwanin-4′-methyl ether 2, β-sitosterol 3, oleanolic acid 4, ursolic acid 5, apigenin 6, β-sitosteryl glucoside 7, p-hydroxyphenyl caffeate 8, caffeic acid 9, shimobashiric acid B 10, methyl rosmarinate 11, butyl rosmarinate 12, luteolin 13, luteolin-7-O-glucoside 14 and rosmarinic acid 15. Complete structural verification of the isolated compounds was achieved by careful inspection of their spectral data including NMR (1D & 2D) and HREIMS.     

A new synthesis of theaspirone,an odiferous principle of tea

A new synthesis of theaspirone (10) is recorded. The key step involves coupling between the organolithium reagent 6, derived from 4-bromo-2-butanol (4), and the monoketal of 4-ketoisophorone (3). Removal of protecting groups and ether cyclization then gave theaspirone 10 and its diastereoisomer 11.     

Benzamide directed ortho metalation : A route to the a/b ring synthon of daunomycinone

The A/B ring synthon 13, previously converted into daunomycinone(6) by Keay and Rodrigo,⁶ has been prepared in seven steps and 38% overall yield using benzamide directed ortho metalation strategy. Significant steps are: the incorporation of a four-carbon Grignard unit (10) into 9, dibal reduction of 11, and intramolecular aldol condensation of the resulting product 12 to give the dihydronaphthalene 13.     

Tulearins A, B, and C; structures and absolute configurations

The relative configuration of tulearin A (1) is determined by X-ray diffraction analysis of a cyclic carbonate derivative 2 and the absolute configuration (2R,3R,5S,8S,9S,15R,17S) from the 9-MTPA-esters 1R and 1S is determined using the modified Mosher’s method. A mechanism for the unexpected formation of carbonate 2 is suggested. Two N-phenyltriazolinedione derivatives 3 and 4 are also prepared. Two additional tulearins, B and C (5 and 6) are isolated in very small amounts and their structures are elucidated by spectroscopic means.     

New total synthesis of (+)-cystothiazole A based on palladium-catalyzed cyclization-methoxycarbonylation

Palladium-catalyzed cyclization-methoxycarbonylation of (2R,3S)-3-methylpenta-4-yne-1,2-diol (6) derived from (2R,3S)-epoxy butanoate 7 followed by methylation gave the tetrahydro-2-furylidene acetate (−)-10, which was converted to the left-half aldehyde (+)-3. A Wittig reaction between (+)-4 and the phosphoranylide derived from the bithiazole-type phosphonium iodide 4 using lithium bis(trimethylsilyl)amide afforded the (+)-cystothiazole A (2).