Asymmetric Synthesis of 3-Substituted 4-Oxoesters Using the SAMP-/RAMP-Hydrazone Method

Based on aldehydes 1a—f or ketone 1g, 3-substituted 4-oxo esters 6a—g were synthesized in three steps in moderate to good overall yield (12—50%) and in excellent enantiomeric excesses (ee >90—>95%) by an Umpolung-strategy employing the SAMP-/RAMP-hydrazone method. The key step in the synthesis is the highly diastereoselective alkylation of lithiated SAMP-hydrazones 3a—g (chiral d²-nucleophiles) with tert-butyl bromoacetate (4) (a²-electrophile) to furnish the alkylated 3-hydrazono tert-butylesters 5a—g in good yields (58—91%) and in excellent diastereomeric excesses (de >90—>98%). Regeneration of the carbonyl functionality by cleavage of the hydrazones 5a—g was accomplished either by acidic hydrolysis or ozonolysis to give the acid labile and oxidation-sensitive 3-substituted 4-oxo esters 6a—g in moderate yields (19—63%) and in excellent enantiomeric excesses (ee >90—>95%). The absolute configuration of compounds 6a—g were assigned by conversion of 4-oxo esters (S)-6d and (R)-6e into their corresponding known 3-substituted λ-butyrolactones (S)-7d and (R)-7e.     

Synthesis of optically active β-hydroxy-β-polyfluoromethyl GABAs

A general synthetic route to polyfluoromethyl containing analogues of GABA—β-hydroxy-β-tri- and difluoromethyl GABAs 9a and 9b was developed, using the corresponding β-alkoxyvinyl polyfluoromethyl ketones—enones 1a and 1b as starting materials. Both enantiomers of the potential biologically active compound 9a were obtained by chiral resolution with (R)- or (S)-phenylethylamine.     

Synthesis of some stereoisomers of (±) - 1 - desmethyldesmotroposantonin methyl ether and related lactones

Alkylation of 7 - methoxy - 8 - methyl - 1 - tetralone (9) with α-bromopropionic acid provided a stereoisomeric mixture of the keto-acid (10). The isomers (10a and 10b) on sodium borohydride reductions afforded respectively the title compounds (12 and 13). Similar reduction of a stereoisomeric mixture of 17, on the other hand, produced two cis-lactones (19 and 20), the hydroxy-acid (30) and the trans-lactone (22). Sodium borohydride reduction of the simple keto-acid (18) furnished initially the cis-lactone (21) and a mixture of hydroxy-acids (31). This hydroxy-acid on lactonisation gave a separable mixture of 21 and 24. The steric effect of the peri-Me group on the stereochemical outcome of sodium borohydride reduction of the keto-acid (10) has been clearly demonstrated. It has also been pointed out that the difference in the NMR signals for C—6 benzylic protons of the C—11 epimeric cis-lactones, reported here and in the literature, may serve as a diagnostic tool for elucidating the stereochemistry of the C—11 Me groups of these lactones.     

Biomimetic α-acylimmonium cyclisations of unactivated olefin

Cyclisation of olefinic ω-ethoxylactams 9-16 leads to ringclosed products in excellent yields. The reaction is weakly acid-catalyzed, in several cases also stereospecific and proceeds at ambient temperature. The structure and configuration of the products are discussed. Possible relationships with other immonium cyclisations and with cationic carbocyclic olefincyclisations are reviewed. The cyclisation of one example—13b—deserves special attention because of the concomitant operation of synchronous and stepwise cyclisation mechanisms.     

Übergangsmetall-substituierte phosphane,arsane und stibane: XXXVI. Diastereomere dreikernkomplexe mit verbrückenden dimethylarsino-, dimethylstibino- oder dimethylbismutino-einheiten

Interaction of the chiral organometallic Lewis bases Cp(CO)(Me₃P)Fe—EMe₂ (E = As, Sb, Bi) (1a–1c) with the norbornadiene metal complex (C₇H₈)Mo(CO)₄ yields the first examples of trinuclear complexes [Cp(CO)(Me₃P)Fe—EMe₂]₂Mo(CO)₄ (2a–2c), bearing two chiral metal atoms separated by a E—Mo—E-linkage. 2a–2c are generated as a mixture of two diastereomers (RS/SR, RR/SS), which gives rise to a resonance doubling in their ¹H and ³¹P NMR spectra. This phenomenon is not observed for the achiral, in part sterically more crowded derivatives [Cp(CO)₂Fe—SbMe₂]₂Mo(CO)₄ (4) and [Cp(CO)₂(Me₃P)Mo—EMe₂]₂Mo(CO)₄ (E = As, Sb (6a, 6b)), which excludes the existence of conformers resulting from restricted rotation about the FeE or MoE bond in the case of 2a–2c.     

Asymmetric nitrogen—41: Stereochemistry of bicyclic 1,2-cis-diaziridines

The twisting of 5- and 6-membered rings in bicyclic cis-diaziridines—1,5-diazabicyclo [3.1.0]hexanes 12–17 and l,6-diazabicyclo[4.1.0]heptane 18—is a rapid process in the time scale of ¹H- and ¹³C-NMR even at -80°. According to the ¹H- and ¹³C-NMR spectra, 1,5-diazabicyclo [3.1.0]hexanes 12,13,15a,15b and 16a,16b do, exist mostly in the boat form ; only the introduction of endo substituents into position 3 or 6 leads to the population of the chair, as is the case with 14 and 17. 2,4-Dialkyl substituted 1,5-diaza- and 1,3,5-triazabicyclo[3.1.0]hexanes are formed via a transition cyclization state similar in its geometry to the initial chair-shaped N-chlorodi(tri)azanes.     

Acetolysis of the trifluoromethanesulphonates of syn-12-hydroxyaldrin and syn-12-hydroxyisodrin and their dihydro derivatives : Reduction in neighbouring double bond participation effected by chlorine substituents

Acetolysis rates of the trifluoromethanesulphonates of two geometric isomers of hexachlorotetracyclo[6.2.1.1^3,6.O^2,7]dodeca-4,9-dien-12-ol (6, 8; syn-12-hydroxyaldrin, syn-12-hydroxy-isodrin) and of two geometric isomers of hexachlorotetracyclo[6.2.1.1^3,6.O^2,7dodec-9-en-12-ol (7,9; syn-12-hydroxy-4, 5-dihydroaldrin, syn-12-hydroxy-4,5-hydroisodrin) have been determined. The results show that neighbouring double bond participation by a —ClCCCl— grouping that is juxtaposed to an incipient secondary carbenium ion (> CH·OSO₂CF₃ is negligible compared with that seen in the non-chlorinated prototypes containing an analogously-situated —CHCH— grouping (e.g.4). The products of acctolysis of 8 and 9 were acetates of the original carbocyclic ring system, but the acctolysis of 6 at 64° yielded, as the sole rearranged product, a hexachloropentacyclo[7.2.1.O^2,8.O^3,5.O⁴]dodecen-6-yl acetatc10. The major products of acetolysis at 64° of 7 were a mixture of two isomeric hexachlorotetracyclol[6.3.1.O^2,9.O^3,7]dodecen-11-yl acetates(17,18) and a hexachloropentacyclo[6.4.0.O^2,10.O^3,7.O^9,11 dodec-4-ene 15; these were each formed via an initial bridging reaction and subsequent rearrangement steps. The factors that dictate the nature of products formed from each compound are discussed, and probable pathways to each are delineated.     

Transition metal 1,3,2-diazagallol derivatives

Reduction of digallane (dpp-bian)Ga—Ga(dpp-bian) (1) (dpp-bian is the 1,2-bis[(2,6-di-isopropylphenyl)imino]acenaphthene dianion) with metallic sodium in THF leads to the formation of gallylsodium (dpp-bian)Ga—Na(thf)₄ (2). Reduction of digallane 1 with dicyclopentadienyltetracarbonyldiiron, vanadocene, and nickelocene furnishes the corresponding gallyl complexes (dpp-bian)Ga—FeCp(CO)₂ (3), (dpp-bian)Ga—VCp₂ (4) and [(dpp-bian)Ga]₂NiCp (5). The reaction of 1 with Cp₂Mn gives a gallium-free complex (dpp-bian)MnCp(dme) (6). Carbonylates [{(dpp-bian)Ga—M(CO)₅}{Na(thf)₂}]₂ (M = Cr (7), W (8)) and [{(dppbian)Ga}₂FeCp(CO)][Na(dme)₃] (9) were obtained by the reaction of carbonyls Cr(CO)₆, W(CO)₆, and [CpFe(CO)₂]₂ with compound 2. Diamagnetic derivatives 3, 7, 8, and 9 were characterized by ¹H NMR spectra. The structures of products 3—9 were established by single crystal X-ray diffraction.     

Asymmetric synthesis of esomeprazole

A highly efficient synthesis of esomeprazole—the (S)-enantiomer of omeprazole—via asymmetric oxidation of prochiral sulphide 1 is described. The asymmetric oxidation was achieved by titanium-mediated oxidation with cumene hydroperoxide (CHP) in the presence of (S,S)-diethyl tartrate [(S,S)-DET]. The enantioselectivity was provided by preparing the titanium complex in the presence of 1 at an elevated temperature and/or during a prolonged preparation time and by performing the oxidation of 1 in the presence of an amine. An enantioselectivity of >94% ee was obtained using this method.     

A synthesis of rhodotorulic acid

A comparative study of the catalytic hydrogenation of benzyloxyamine hydrochloride (2a·HCl), benzyl benzohydroxamate (2b), and benzohydroxamic acid (3b) using PdC as a catalyst has disclosed that 2a·HCl smoothly undergoes the hydrogenolytic cleavage at both the benzyl—O and NO bonds, whereas 2b almost selectively suffers benzyl—O cleavage. The use of the benzyl group for protecting a hydroxamic acid function, suggested by the hydrogenolysis study, was embodied in the synthesis of rhodotorulic acid (1) starting with the reaction of 2a with bromide 5 to give 8. The key intermediate l-9 was conveniently prepared by the selective, asymmetric deacetylation of 8 using Taka-diastase. Conversion of l-9 into amino ester l-13 through the N^α-protected amino acid (l-11) and ester l-12 and coupling of l-11 with l-13 yielded dipeptide ll-14. Removal of the tert-butoxycarbonyl group from ll-14 and cyclization of the resulting amino ester produced the penultimate benzyl hydroxamate (ll-15), which was debenzylated selectively with PdC and hydrogen to furnish 1.     

On papaver bracteatum—XIV: Ready access to benzylidene phthalimidine compounds from rhoeadine alkaloid-derived nitriles

The $\text{B}\text{D}$trans lactole alpinigenine (1a) isolated from Papaver bracteatum Lindl. was shown to form the oxime 2a which in turn was transformed to the nitrile 3a by dehydration, the methiodide 4a, and — by treatment with alkali under mild conditions — to the benzylidene phthalimidine derivative 5a, whose structure was elucidated by spectral analysis as well as oxidative fragmentation into 6 and 7.The unique reaction leading to 5a apparently is bound with certain structural prerequisites inherent to 3a, including stereochemistry. When cis-alpinigenine (1b) was subjected to the same sequence, little of 5a accordingly could be obtained, and even none of any phthalimidine was formed from the non-acetoxylated nitrile 11.     

Spectroelectrochemistry and localization of added electrons in ruthenium (II) mixed-ligand complexes

The ruthenium (II) mixed-ligand complexes cis-[Ru(bpy)₂(NCS)₂] (I), [Ru(bpy)₂(pn)]²⁺ (II) and [Ru(bpy)₂(phen)]²⁺ (III) (bpy, 2,2′-bipyridine; pn, 1,2-diaminopropane; phen, 1,10-phenanthroline) were subjected to two (for I and II), and three (for III) stepwise, one-electron reductions, and one-electron oxidations (all fully reversible); the products were studied in situ by solution UV—vis-near IR spectroscopy. The first two reductions took place in all cases on separate bpy ligands, while the third reduction of III took place on phen. Bands of the reduced species in the near IR—vis region are observed and assigned to anion radical ligands. Novel features of the LMCT bands of the oxidized species are presented and discussed.     

Decrease of the XPS shake-up intensity on going from paranitroaniline to nitro-amino azabenzenes

The intensity of the shake-up satellites present in the solid-phase XPS spectra of paranitroaniline (1), 2-amino-5-nitropyridine (2) and 2-amino-5-nitropyrimidine (3) decreases from (1) to (3) in agreement with CNDO/S CI calculations. The HOMO—LUMO energy gap appears to be responsible for the observed trend.     

Characterization and cytotoxicity of ellagitannins from Stachyurus praecox fruit

This study aimed to characterize and evaluate the cytotoxicities of ellagitannins from S. praecox fruit. Fractionation of an acetone extract of the fruit led to isolation of five new ellagitannins—stachyuranin D (15), stachyuranin E (16), stachyuranin F (17), stachyugluconin (18), and stachyuglyconin (19)—along with seven ellagitannins previously isolated from S. praecox leaves and seven known ellagitannins isolated from Stachyuraceae for the first time. Two-dimensional NMR and other spectroscopic methods enabled complete elucidation of the structures of the new compounds. Structure of flavanoellagitannin (16) was confirmed by ¹H NMR comparison with synthetic analogs. The configuration of stachyuglyconin (19) with a C₈-aldonic acid core was established with the aid of density functional theory calculations. A MTT assay revealed 5-desgalloylpterocarinin A (11) and hippophaenin B (9) had the highest cytotoxicities among the compounds against HeLa (IC₅₀ = 35.35 μM) and HepG2 (IC₅₀ = 60.00 μM) cells, respectively.     

Substrate recognition by norovirus polymerase: microsecond molecular dynamics study

Molecular dynamics simulations of complexes between Norwalk virus RNA dependent RNA polymerase and its natural CTP and 2dCTP (both containing the O5′–C5′–C4′–O4′ sequence of atoms bridging the triphosphate and sugar moiety) or modified coCTP (C5′–O5′–C4′–O4′), cocCTP (C5′–O5′–C4′–C4′′) substrates were produced by means of CUDA programmable graphical processing units and the ACEMD software package. It enabled us to gain microsecond MD trajectories clearly showing that similar nucleoside triphosphates can bind surprisingly differently into the active site of the Norwalk virus RNA dependent RNA polymerase. It corresponds to their different modes of action (CTP—substrate, 2dCTP—poor substrate, coCTP—chain terminator, cocCTP—inhibitor). Moreover, extremely rare events—as repetitive pervasion of Arg182 into a potentially reaction promoting arrangement—were captured.     

Synthesis and characterization of a biphenyl-linked hemicryptophane and an endohedral cobalt(II) complex

Hemicryptophanes are covalent molecular cages, constructed from a cyclotriveratrylene-based host unit and a functional unit linked by covalent spacers, which have been designed to accommodate endohedral functionalities in the cavity. In this study, the synthesis and characterization of the rigid, biphenyl-linked hemicryptophane 1 were investigated by NMR, ESI-MS, and X-ray crystallography. The structure of the inclusion complex, in which a dichloromethane molecule was constructed encapsulated within 1, was characterized by X-ray crystallography. An endohedral, cobalt(II) hemicryptophane complex 2 was also synthesized and characterized ESI-MS and X-ray crystallography. The X-ray crystal structure of 2 showed that the biphenyl-linked hemicryptophane had three components—a molecule each of chloroform and acetonitrile, and a cobalt(II) ion—within its cavity.     

The structure of the products of coupling aryldiazonium salts with phenacylthiocyanates. Correction of literature reports

A variety of coupling products of phenacylthiocyanates 1a—d with aryldiazonium chlorides is reported. The i.r., u.v.¹³C NMR as well as the chemical behaviour of the coupling products clearly reveal that they are hydrazones (7) and not thiadiazol-2-imines (5) as previously reported.     

Hydrogen transfer processes in the formation of cationic η5 -dienyl complexes of ruthenium(II): X-ray structure of [Ru(1-5-η-cyclooctadienyl)(PMe2Ph)3][PF6]

The cations [Ru(1—3:5—6-η-C₈H₁₁)(η⁶ -1,3,5-cyclooctatriene)]⁺ (2) and [RuH(COD)L₃]⁺ (5) (COD = cycloocta-1,5-diene, L = PMe₂Ph, AsMePh₂) are convenient precursors to a range of η⁵ -dienyl complexes of ruthenium(II); evidence for hydrogen transfer processes is presented.     

A concise,stereocontrolled synthesis of spectinomycin

A simple and concise synthesis of the antibiotic spectinomycin is described. The key step comprises a reaction cascade initiated by the β-selective 5-O-glycosylation of an N,N-blocked myo-1,3-inosadiamine 10 with a suitable actinospectosyl donor—the d-glucose-derived enol benzoate of 4,6-dideoxy-α-d-hex-3-enulosyl chloride 5—which is spontaneously followed by regio- and stereospecific cyclo-hemiketalization and a 3-O→2-O-benzoyl group migration to directly elaborate the cis–cisoid–trans-fused pyran–dioxane–cyclohexane framework of 1. The approach is flexible enough to be applied to other inosadiamines towards the generation of novel spectinomycin analogues.     

C-Nitroso compounds—XXXV : Reaction of organometallic compounds with 1-chloro-1-nitroso-2,2,6,6-tetramethylcyclohexane

Reaction of Grignard reagents and organolithium compounds (RM) with the congested 1-chloro-1-nitroso-2,2,6,6-tetramethylcyclohexane 1 leads to the formation of significant amounts of the reduction product 2,2,6,6-tetramethylcyclohexanone oxime 3 (61–90%) together with the corresponding oxime O-R ether 4 (0–11%). Attack on nitrogen is unimportant as shown by very low yields of nitrone. Formation of the products is rationalised with a pathway involving transfer of an electron from RM to 1. This leads—after separation of MCI—to a radical pair consisting of R and the relatively stable iminoxy radical 2 (Schemes 1 and 2). Combination of these radicals explains formation of oxime ether 4 and nitrone 5, while reaction of iminoxy radical 2 with excess of RM can give oxime 3. Reactive radicals R (i.e. Me, Ph, and to a minor extent n-Bu) are furthermore capable of abstracting hydrogen from the solvent (diethyl ether, toluene, or cumene), and the solvent derived radicals can also combine with 2 on oxygen, under formation of oxime ether (26% of 6a). The corresponding benzyl- and cumyl ethers 6b and 6c are only formed in trace amounts because dimerisation of benzyl radicals (7%) and cumyl radicals (22%) is favoured.