Umsetzungen von Dilithio-nitroalkanen und -allylnitroderivaten mit Carbonylverbindungen

Reactions of dilithio-nitroalkanes and dilithio-allynitroalkanes with carbonyl compounds Primary nitro compounds can by acylated via dilithium derivatives 5 with carbonic-acid derivatives to give α-nitro esters 6a – i and with carboxylic-acid esters and anhydrides to give α-nitroketones 6j – q . In the reaction of 1-nitro-1-buten with two mol-equiv. of butyllithium, the dilithium compound 10 is formed by successive Michael-addition and nitronate deprotonation. Dilithium derivatives 5 also react with ketones and benzaldehyde (→ 18a – g ); the nitro aldols 25 and 26 are likewise formed by addition of doubly deprotonated allylic nitro compounds. Some of the products have been further transformed by reduction or by Nef-reactions to the hydrochloride of the α-amino-acid 26 , to 2-amino-alcohols 28a and 28b , to α-hydroxyamino-acid esters 27a – c , to α-hydroxyimino esters 35 and 36 , to α-hydroxyimino ketones 31 and 33 , to the α-diketone 34 , and to the α-keto ester 37 .     

1,5-Dipolare Elektrocyclisierung von Acyl-substituierten ‘Thiocarbonyl-yliden’ zu 1,3-Oxathiolen

1,5-Dipolar Electrocyclization of Acyl-Substituted ‘Thiocarbonyl-ylides’ to 1,3-Oxathioles The reaction of α-diazoketones 15a, b with 4,4-disubstituted 1,3-thiazole-5(4H)-thiones 6 (Scheme 3), adamantanethione ( 17 ), 2,2,4,4-tetramethyl-3-thioxocyclobutanone ( 19 ; Scheme 4), and thiobenzophenone ( 22 ; Scheme 5), respectively, at 50–90° gave the corresponding 1,3-oxathiole derivatives as the sole products in high yields. This reaction opens a convenient access to this type of five-membered heterocycles. The structures of three of the products, namely 16c, 16f , and 20b , were established by X-ray crystallography. The key-step of the proposed reaction mechanism is a 1,5-dipolar electrocyclization of an acyl-substituted ‘thiocarbonyl-ylide’ (cf. Scheme 6). The analogous reaction of 15a, b with 9H-xanthen-9-thione ( 24a ) and 9H-thioxanthen-9-thione ( 24b ) yielded α,β-unsaturated ketones of type 25 (Scheme 5). The structures of 25a and 25c were also established by X-ray crystallography. The formation of 25 proceeds via a 1,3-dipolar electrocyclization to a thiirane intermediate (Scheme 6) and desulfurization. From the reaction of 15a with 24b in THF at 50°, the intermediate 26 (Scheme 5) was isolated. In the crude mixtures of the reactions of 15a with 17 and 19 , a minor product containing a CHO group was observed by IR and NMR spectroscopy. In the case of 19 , this side product could be isolated and was characterized by X-ray crystallography to be 21 (Scheme 4). It was shown that 21 is formed – in relatively low yield – from 20a . Formally, the transformation is an oxidative cleavage of the C?C bond, but the reaction mechanism is still not known.     

Asymmetrische Michael-Additionen. Stereoselektive Alkylierung chiraler,nicht racemischer Enolate durch Nitroolefine. Herstellung enantiomerenreiner γ-Aminobuttersäure- und Bernsteinsäure-Derivate

Asymmetric Michael-Additions. Stereoselective Alkylation of Chiral, Non-racemic Enolates by Nitroolefins. Preparation of Enantiomerically Pure γ-Aminobutyric and Succinic Acid Derivatives Chiral, non-racemic lithium enolates ( E , F , G ) of 1,3-dioxolan-4-ones, methyl 1,3-oxazolidin-4-carboxylates, methyl 1,3-oxazolin-4-carboxylates, 1,3-oxazolidin-5-ones, and 1,3-imidazolidin-4-ones derived from (S)-lactic acid ( 2a ), (S)-mandelic acid ( 2b ), and (S)-malic acid ( 2c ), or from (S)-alanine ( 10 ), (S)-proline ( 11 ), (S)-serine ( 12 ), and (S)-threonine ( 13 ), are added to nitroolefins. Michael adducts ( 3 – 9 , 14 – 18 ) are formed (40–80%) with selectivities generally above 90% ds of one of the four possible stereoisomers. Conversions of these nitroalkylated products furnish the α-branched α-hydroxysuccinic acids 28 and 29 , the α-hydroxy-γ-amino acid 25 , the α,γ-di-amino acid 32 , the substituted γ-lactames 19 – 22 , and the pyrrolidine 23 . The relative and absolute configuration of the products from dioxolanones and nitropropene are derived by chemical correlation and NOE measurements indicating that the steric course of reaction is to be specified as 1k, ul-1,3. The mechanism is discussed.     

Michael Reactions of α-Unsubstituted Trisubstituted 1H-Pyrroles

To obtain stable derivatives of α-unsubstituted pyrroles, the reaction of the test pyrrole 9 with a series of chalcones 14a – h were studied. Michael adducts 16b – h could be isolated. In order to synthesize coloured derivatives, the reaction of different pyrroles 9, 21, 23 , and 25 with diphenylpropynone 19 was investigated. In these cases, too, Michael-addition products were formed. The intense absorption band around 400 nm makes the identification of these derivatives easy.     

Synthese von 3-Dimethylamino-3a,4,5,7a-tetrahydro-1H-iso-indol-1-onen durch intramolekulare Diels-Alder-Reaktion

Synthesis of 3-Dimethylamino-3a,4,5, 7a-tetrahydro-1H-isoindol-1-ones by Intramolecular Diels-Alder Reaction Thermolysis of N²-acylamidines, the acyl group of which derives from an α,β,γ,δ-unsaturated carboxylic acid ( 2, 5 – 7 ), yields 3-dimethylamino-3a,4,5,7a-tetrahydro-1H-isoindol-1-ones ( 3,8 – 10 , Schemes 1 and 3) in 63–78%. Only the thermodynamically controlled cis-fused ring system is formed. The starting materials are readily available by the reaction of 3-dimethylamino2H-azirines ( 1 and 4 ) and carboxylic acid chlorides.     

Matched/Mismatched Interactions in Chiral Brønsted Acid-Catalyzed Glycosylation Reactions with 2-Deoxy-Sugar Trichloroacetimidate Donors

The stereochemical outcome of glycosylation reactions of 2-deoxy-sugar trichloroacetimidates promoted by chiral Brønsted acids is shown to be dependent on both the chirality of the catalyst and the configuration of the leaving group. High levels of selectivity (1:16 α:β) can be obtained with (S)-catalysts and an α-trichloroacetimidate donor. Conversely, (R)-catalysts require longer reaction times and provide the product in much lower selectivity (6.6:1 α:β). These observations demonstrate that stereochemical “match” and “mismatch” between donor and acceptor are important factors in chiral Brønsted acid-promoted glycosylations.     

Hydroxyalkylierungen von Cystein über das Enolat von (2R,5R)-2(tert-Butyl)-1-aza-3-oxa-7-thiabicyclo[3.3.0]octan-4-on und unter Selbstreproduktion des Ciralitätszentrums

Hydroxyalkylations of Cysteine through the Enolate of (2R,5R)-2(tert-Butyl)-1-aza-3-oxa-7-thiabicyclo[3.3.0]octan-4-one with Self-Reproduction of the Center of Chirality The heterobicyclic compound 1 specified in the title is readily prepared as a single stereoisomer from (R)-cysteine, formaldehyde, and pivalaldhyde. While it is not possible to generate the enolate 10 from 1 qunatitatively – due to β-elimination of thiolate (→6) – an in-situ addition to aromatic aldehydes such as benzaldehydes (→13–16) , pyrrol-, furan-, and thiophen-2-carbaldehydes (→17–19) , pyridine-3-carbaldehyde (→21) , as well as to other non-enolizable aldehydes like cinnamaldehyde (→22) , can be achieved in yields of ca. 50%. The adducts ( 8 and 9 ) of lithium diisopropylamide or t-butoxide to these aldehydes are acting, probably as bases for deprotonation and as in-situ sources of the electrophilic aldehyde species (cf. 11, 12 ). - Of the four possible diastereoisomeric products, one is usually formed with >90% selectivity (Table). It is assumed that the preferred stereochemical course of the reaction corresponds to that observed previously with the analogous proline-derived enolate (See 23,24 ). A chemical correlation with l-α-methyl-β-phenylserine (25) proves the relative configuration of the benzaldehyde adduct 13 . All hydroxyalkylated products (13–19, 21, 22) are obtained as crystalline, diastereoisomerically pure compounds and are fully characterized. – The benzaldehyde derivative 13 was used to exemplify the various possible transformations of these products to monocyclic or acyclic amino-acid derivatives such as the oxazolidionenes 26 and 29 (cleavage of the ring containing the S -atom), the thiazolidines 28 , 31 , and 32 (cleavage of the cyclic N,O-acetal) and the α-branched cysteine 27 and the phenylserines 25 and 30 (cleavage of both rings to give open-chain aminoacids).     

The reaction of aryl iodides with hindered α,β,γ,δ-dienones in the presence of the [Pd(OAc)2(PPh3)2]-trialkylammonium formate reagent

Hindered α,β,γ,δ-dienones have been shown to react with aryl iodides in the presence of the [Pd(OAc)₂(PPh₃)₂]-trialkylammonium formate reagent to give mainly 1,4-conjugate addition type products. The α,β,γ,δ-dienones were prepared through reaction of the corresponding vinyl triflates with α,β-enones in the presence of Pd(OAc)₂, K₂CO₃, and tetrabutylammonium chloride at room temperature.     

An efficient synthetic method for Z-fluoroalkene dipeptide isosteres: Application to the synthesis of the dipeptide isostere of Sta-Ala

Reaction of γ,γ-difluoro-α,β-enoates having a δ-hydroxyl group with trialkylaluminum (R₃Al) was found to be promoted by CuI·2LiCl and to proceed in SN2′ manner giving rise to the α-alkylated (Z)-γ-fluoro-β,γ-enoates, while reductive defluorination of γ,γ-difluoro-α,β-enoates with Me₂CuLi followed by reaction with alkyl halides provided the corresponding (Z)-α-alkylated products in high yields. The latter reaction was applied to the preparation of the dipeptide (Z)-fluoroalkene isostere of Sta-Ala, which is the central dipeptide unit in Pepstatin, a natural inhibitor of aspartate proteases.     

Heterogeneous versus Homogeneous Copper(II) Catalysis in Enantioselective Conjugate‐Addition Reactions of Boron in Water

We have developed Cu^II‐catalyzed enantioselective conjugate‐addition reactions of boron to α,β‐unsaturated carbonyl compounds and α,β,γ,δ‐unsaturated carbonyl compounds in water. In contrast to the previously reported Cu^I catalysis that required organic solvents, chiral Cu^II catalysis was found to proceed efficiently in water. Three catalyst systems have been exploited: cat. 1: Cu(OH)₂ with chiral ligand L1 ; cat. 2: Cu(OH)₂ and acetic acid with ligand L1 ; and cat. 3: Cu(OAc)₂ with ligand L1 . Whereas cat. 1 is a heterogeneous system, cat. 2 and cat. 3 are homogeneous systems. We tested 27 α,β‐unsaturated carbonyl compounds and an α,β‐unsaturated nitrile compound, including acyclic and cyclic α,β‐unsaturated ketones, acyclic and cyclic β,β‐disubstituted enones, acyclic and cyclic α,β‐unsaturated esters (including their β,β‐disubstituted forms), and acyclic α,β‐unsaturated amides (including their β,β‐disubstituted forms). We found that cat. 2 and cat. 3 showed high yields and enantioselectivities for almost all substrates. Notably, no catalysts that can tolerate all of these substrates with high yields and high enantioselectivities have been reported for the conjugate addition of boron. Heterogeneous cat. 1 also gave high yields and enantioselectivities with some substrates and also gave the highest TOF (43 200 h^?1) for an asymmetric conjugate‐addition reaction of boron. In addition, the catalyst systems were also applicable to the conjugate addition of boron to α,β,γ,δ‐unsaturated carbonyl compounds, although such reactions have previously been very limited in the literature, even in organic solvents. 1,4‐Addition products were obtained in high yields and enantioselectivities in the reactions of acyclic α,β,γ,δ‐unsaturated carbonyl compounds with diboron 2 by using cat. 1, cat. 2, or cat. 3. On the other hand, in the reactions of cyclic α,β,γ,δ‐unsaturated carbonyl compounds with compound 2 , whereas 1,4‐addition products were exclusively obtained by using cat. 2 or cat. 3, 1,6‐addition products were exclusively produced by using cat. 1. Similar unique reactivities and selectivities were also shown in the reactions of cyclic trienones. Finally, the reaction mechanisms of these unique conjugate‐addition reactions in water were investigated and we propose stereochemical models that are supported by X‐ray crystallography and MS (ESI) analysis. Although the role of water has not been completely revealed, water is expected to be effective in the activation of a borylcopper(II) intermediate and a protonation event subsequent to the nucleophilic addition step, thereby leading to overwhelmingly high catalytic turnover.     

Synthetische Verwendung von Epoxynitronen. II. Synthese von Steroid-α-methyliden-γ-lactonen

Synthetic application of epoxynitrones. II. Syntheses of steroidal α-methylidene-γ-lactones This communication describes the application of the epoxynitrone/CF₃SO₃SiR₃ → 1,2-oxazine annelation-reaction [1] to the syntheses of steroidal α-methylidene-γ-lactones from olefines, e.g. 12 → 14a/b → 16a/b → 18a/b → 20 → 22 (Scheme 2).     

Synthesis of δ-cyclohexyl- and δ,δ-alkylene-α,α-dicarbonyl-substituted dienes and study of their valence isomerization

β-Cyclohexylacrolein, β-cyclohexylmethacrolein, or α-cycloalkylidenalkanals were condensed with methyl acetoacetate or dimethyl malonate to give the δ-cyclohexyl- and δ,δ-alkylene-substituted α,α-dicarbonyl-containing α,β∶γ,δ-dienes. The structures of the reaction products were studied using¹H NMR,¹³C NMR, and UV spectroscopy. The diene keto esters bearing no substituents at the γ-position were shown to be in fact three-component equilibrium mixtures comprised ofE- andZ-isomers of the diene (at the α,β bond) and a corresponding 2H-pyran. On the other hand, for keto esters with a Me group at the γ-position the equilibrium is shifted entirely to the 2H-pyrans. In contrast with the keto esters, dienic diesters exist only in the open form.     

Towards the development of oxadiazinanones as chiral auxiliaries: synthesis and application of N3-haloacetyloxadiazinanones

Oxadiazinanones derived from (1R,2S)-ephedrine and (1R,2S)-norephedrine were employed in the asymmetric α-halo aldol reaction. The optimized yields and diastereoselectivities for the ephedrine based oxadiazinanone aldol reaction ranged from fair to good. The ephedrine based aldol adducts were hydrolyzed to afford the α-bromo-β-hydroxycarboxylic acids. The absolute stereochemistry and enantiomeric purity of these products were determined by chiral HPLC and specific rotation measurements.     

Zur Reaktionsweise von Enaminen mit Cyclopropenonen I. Einsatz von Cyclododecanon-Enamin

Monomethyl-, dimethyl-, di-n-propyl- and diphenyl-cyclopropenone ( 6 to 9 ) have been reacted with 1-(N-pyrrolidino)-cyclododecene ( 5 ) and three types of products isolated. The major products (40–7% yield) were shown to have the 3 -(cyclododec-1′-E-enyl)Z-/or E-acryl-pyrrolidide structure ( 12 , 13 / 14 , 15 / 16 , 17 ) by their spectral properties and lithium aluminium hydride reductions as well as, in one case ( 13 ), by an alternative synthesis of a stereomer ( 34 ) via 1-(cyclododec-E-ene)-carboxaldehyde ( 29 ) and a Wittig reaction. These ‘amides’ are the result of a novel reaction, called ‘C, N-insertion’. In the reactions of the symmetrical cyclopropenes 7 to 9 with 5 , the minor products (6–10%) proved to have the 2,4-disubstituted cyclopentadeca-4-E-en-1,3-dione structures 38 to 40 . These ‘β-diketones’ are considered to be the hydrolysed forms of the intermediate 1-(N-pyrrolidino)-cyclopentadeca-1,4-dien-3-ones ( 45 ).They are formed by reactions (called ‘C,C-insertions’), which represent the first cases of direct ring expansions by three carbon atoms. Such ‘C,C-insertions’ have been postulated previously by other authors. However, their products do not behave like precursors of our ‘β-diketones’ but rather like our ‘amides’. It is proposed therefore, that a reinterpretation of these reactions in the literature must be considered in the light of our ‘C, N-insertion’. In one reaction ( 8 + 5 ) a bicyclo[10. 3. 0]pentadeca-12-en-14-one dericative 42 was found in 10% yield. This type of product and reaction (called ‘condensation’) has been reported previously. A suggestion is made for a systematic representation of the several types of reactions, which cyclopropenones can undergo with enamines. – Mixing 9 + 5 in the cold produced an intermediate, which insomerised on heating to the ‘amide’ 17 . Its properties are compared with those of recently described similar ‘primary adducts’ and the latter are reexamined in the light of the new product interpretations reported in this paper. A novel structure is considered for this intermediate, that a of cycle ‘ammonium acylid’ 51 . An attempt is made at the formulation of other possible intermediates.     

Asymmetric Alkylations of a Sultam-Derived Glycine Equivalent: Practical preparation of enantiomerically pure α-amino acids

Alkylation of the chiral glycine derivative 2 with “activated” organohalides under ultrasound-assisted phasetransfer catalysis or with activated and nonactivated organohalides in anhydrous medium provides (mostly crystalline) alkylation products 3 . Acidic hydrolysis of the pure products 3 gives (aminoacyl)sultams 4 which by mild saponification furnish pure α-amino acids 5 in good overall yields from 2 , along with recovered auxiliary 1 (Scheme 1). Pure ω-protected α,ω-diamino acids and α-amino-ω-(hydroxyamino)acids 12–16 are readily accessible from (ω-haloacyl)sultams 3 via reaction with N-nucleophiles followed by acidic and basic hydrolyses (Scheme 2). A reliable determination of the enantiomeric purity of α-amino acids using HPLC analysis of their N-(3,5-dinitrobenzoyl)prolyl derivatives 17 is presented.     

Stereoselective synthesis of 3-azido-2,3-dideoxy-D-ribose derivatives and its utilization for the synthesis of anti-HIV nucleosides

Detail account of the synthesis of 3′-azido nucleosides utilizing 3-azido-2,3-dideoxy-D-ribose derivative 7 as the key intermediate was described. The key intermediate 7 was synthesized from D-mannitol in 8 steps in a preparative scale. The Michael reaction of the azide group with α,β-unsaturated-γ-butyrolactone 4 was affected by the steric bulkiness of the substituent at the 5-O position. A bulky t-butyldiphenylsilyl substitution at 5-O gave almost exclusively the α-azido adduct 5b , while unsubstitution at 5-O produced 1:1 mixture of α-and β-adducts. The ratio of α to β anomers in the condensation between azido acetate 7a and pyrimidine bases for the preparation of AZT and AZDU was greatly influenced by the solvent and the Lewis acid catalyst used. In the synthesis of 12 (AZDU, CS-87), the combination of dichloroethane and trimethylsilyl triflate gave an optimal result, while in the case of 14 (AZT), various conditions gave similar ratio of α,β anomers. The azido intermediate 7b was also utilized for the synthesis of several 3′-azido purine-like nucleosides 16–27 . The glycosylation was also affected by the Lewis acid catalyst. Boron trifluoride etherate gave the desired N₁-glycosylated compounds in which the α-anomer was major, but other catalysts such as trimethylsilyl triflate or stannic chloride produced N₂-glycosylated compounds as the major products. The newly synthesized purine-like compounds have been tested against HIV, however, none of them showed any significant activity.     

Kinetic and thermodynamic aspects in the 1,3-dipolar cycloaddition of five-membered cyclic nitrones to α,β-unsaturated γ- and δ-lactones

The 1,3-dipolar cycloaddition of five-membered ring nitrones to the α,β-unsaturated δ-lactones is kinetically controlled, whereas the same reactions involving γ-lactones, upon heating and prolonged reaction times, display visible reversibility of the reaction and as the consequence, the formation of the more stable, thermodynamic products can be observed. Owing to this and to the high stereoselectivity of the cycloaddition, δ-lactones can be used for kinetic resolution of racemic nitrones whereas γ-ones cannot. In addition the reversibility of the cycloaddition, as well as racemization of 5-substituted 2-(5H)-furanones (γ-lactones), complicates the composition of the post-reaction mixtures and may lead to the formation of partially racemic adducts. The possible asymmetric transformation of cycloaddition involving γ-lactones, which eventually provide the most stable thermodynamic products in high yield, cannot be performed due to the low stability of cyclic nitrones which undergo decomposition.     

Formation of T‐Shaped versus Charge‐Transfer Molecular Adducts in the Reactions Between Bis(thiocarbonyl) Donors and Br2 and I2

The reactions of 4,5,6,7‐tetrathiocino‐[1,2‐b:3,4‐b′]‐1,3,8,10‐tetrasubstituted‐diimidazolyl‐2,9‐dithiones (R₂,R′₂‐todit; 1 : R=R′=Et; 2 : R=R′=Ph; 3 : R=Et, R′=Ph) with Br₂ exclusively afforded 1:1 and 1:2 “T‐shaped” adducts, as established by FT‐Raman spectroscopy and single‐crystal X‐ray diffraction in the case of complex 1? 2 Br₂. On the other hand, the reactions of compounds 1 – 3 with molecular I₂ provided charge‐transfer (CT) “spoke” adducts, among which the solvated species 3? 2 I₂ ? (1?x)I₂ ? x CH₂Cl₂ (x=0.94) and ( 3 )₂ ? 7 I₂ ? x CH₂Cl_2, (x=0.66) were structurally characterized. The nature of all of the reaction products was elucidated based on elemental analysis and FT‐Raman spectroscopy and supported by theoretical calculations at the DFT level.     

Zur heterogenkatalytischen Oxydation und Ammoxydation von Isobuten. 5. Gasphasenoxydation von Methacrolein zu Methacrylsäure an definierten 1:1-Vanadiumphosphaten

On the Heterogen-Catalytical Oxidation and Ammoxidation of Isobutene. 5. Gas-Phase Oxidation of Methacrolein to Methacrylic Acid on Definite 1:1 Vanadium Phosphates For the Oxidation of Methacrolein (MA) to Methacrylic Acid (MAA) definite 1:1 vanadium phosphates were used as test catalysts. (V^IVO)₂P₂O₇ ( 1 ) is directing the reaction with high selectivity to MAA. On using the V^V monophosphates α-( 2 ) and β-VOPO₄ ( 3 ), a valence-mixed “H-V/P mica” (with α-based structure; 46.5% V^IV portion) ( 4 ), and also the new phosphate V^IVO(HPO₄) ( 5 ), however, only a modest selectivity is observed. Whereas the diphosphate 1 was found to be unchanged after the catalytical reaction, in the case of the monophosphates solid state reactions occured during the catalysis: 2 was reduced to a H-V/P mica ( 6 ) with 29% V^IV portion, 4 to the hemi-hydrate V^IV O(HPO₄) · 0.5 H₂O ( 7 ); and from 3 , as new compounds, 5 (see above) and a V^III/V^IV phosphate ( 8 ) were formed. On preparing 5 as a pure phase and using it for the catalysis it mostly remained unchanged; only a minor part was reduced to 8 . – The catalytical action of 1 is discussed.     

Carboxylate Catalyzed Isomerization of β,γ-Unsaturated N-Acetylcysteamine Thioesters**

We demonstrate herein the capacity of simple carboxylate salts – tetrametylammonium and tetramethylguanidinium pivalate – to act as catalysts in the isomerization of β,γ-unsaturated thioesters to α,β-unsaturated thioesters. The carboxylate catalysts gave reaction rates comparable to those obtained with DBU, but with fewer side reactions. The reaction exhibits a normal secondary kinetic isotope effect (k_1H/k_1D=1.065±0.026) with a β,γ-deuterated substrate. Computational analysis of the mechanism provides a similar value (k_1H/k_1D=1.05) with a mechanism where γ-reprotonation of the enolate intermediate is rate determining.