Dérivés de sucres à groupement gem-dihalogénoéthényle

Carbohydrate Derivatives Bearing a gem-Dihalogenoethenyl Group Treated with the appropriate Wittig reagent, aldehydosugar derivatives ( 1–13 ) led in good to excellent yields to the expected gem-difluoro, gem-chlorofluoro-and/or gem-dichloroenoses ( 14–29 ). Examples of their dibromo analogues had been previously described (see e.g. [1]) but the diiodo derivatives could not be isolated, The influence of the conditions on the yields is reported as well as spectroscopic properties (particularly the long-range ¹³C, ¹⁹F- and ¹H, ¹⁹F-coupling constants) of these new enoses.     

Dérivés d'énose- et d'ynosephosphonates et composés voisins. Communication préliminaire

Derivatives of enose- and ynosephosphonates and related compounds. Preliminary communication The gem-dibromo terminal enoses 1 and 7 are convenient sources of glycosylacetylenes which upon reaction with phosphorus electrophiles gave the phosphorusbearing acetylenic sugars 4, 5 and 8 . Compounds 5 and 8 underwent cycloaddition reactions leading to isoxazolyl-C-glycosides 6 and 9 respectively. The nitroolefinic sugar derivative 11 gave upon bromination-dehydrobromination the first example of a new kind of potentially useful synthetic intermediates, the gem-bromonitroenose 12 . The enosephosphonate 13 was also prepared from 11 . The diglycosylhydroxylamine 18 represents another type of phosphorus-bearing acetylenic sugar derivative. Some ¹H- and ¹³C-NMR. data relative to the new types of phosphorus-containing sugar derivatives synthesized are given.     

Utilisation d'ylides du phosphore en chimie des sucres,X. Synthèse stéréospécifique de l'épimère en C3 du streptose et d'autres sucres ramifiés,dérivés de désoxy-5-pentoses, à groupements gem-hydroxy-formyle ou gem-hydroxy-hydroxyméthyle

The synthesis of branched-chain sugars of the gem-hydroxy-formyl and the gem-hydroxy-hydroxymethyl types is described. A 5-deoxy-1,2-O-isopropylidene-furanos-3-ulose is treated with cyanomethylene-triphenyl-phosphorane, yielding the two geometrical isomers of the corresponding branched-chain unsaturated sugar. Cis-dihydroxylation(KMnO₄) of these cyanomethylenic compounds affords stereoselectively and in high yield the gem-hydroxy-formyl branched chain sugars whose formyl group is on the more hindered face of the furanose ring. The hydroxymethyl analogues of the latter compounds are readily prepared by their borohydride reduction. This method constitutes a new general route to type A branched-chain sugars epimeric at the branching-point with the sugars which would have been obtained by the classical procedure involving Grignard reagents.     

Chimie et pharmacologie de l'apiose III. Synthèse et propriétés de l'hydrate de l'O-isopropylidène-1, 2-tétrosulo-3-furannose

Ruthenium tetroxide oxidation of 1, 2-O-isopropylidene-β-D -threofuranose affords, besides the known 1, 2-O-isopropylidene-α-L -glycero-tetros-3-ulofuranose, a lactone. The tetrosulose is easily hydrated to the corresponding gem-diol whose dehydration on molecular sieves leads to a branched-chain dimer. Lead tetraacetate oxidation of 1, 2-O-isopropylidene-α-L -glycero-tetros-3-ulofuranose p-nitrophenylhydrazone leads quantitatively, to a gem-azoacetate, a new synthetic intermediate in carbohydrate chemistry. The 3-O-acetyl-1, 2-O-isopropylidene-α-L -glycero-tetr-3-enofuranose is easily obtained from the gem-diol. A highly stereoselective procedure is described to prepare the 3-O-acetyl-1, 2-O-isopropylidene-α-L -3, 4-exo-D₂-erythrofuranose.     

C-Glycosides V: Données mécanistiques sur l'halogénation d'hydrazones et d'oximes dérivées de sucres. Communication préliminaire

The bromination of aldehydo-sugars p-nitrophenylhydrazones has been studied and the gem-bromo-azo intermediates isolated and characterized in some cases. In the same way, in the chlorination of aldehydo-sugars oximes gem-chloro-nitroso intermediates have been obtained and in some instances isolated. These observations support a S_E2′ mechanism for such reactions.     

Nouveaux types de sucres acétyléniques. Communication préliminaire

Novel types of acetylenic sugars The coupling, following Cadiot's procedure, of a 6-bromo-5,6-dideoxy-1,2-O-isopropylidène-3-O-methyl-α-D -xylo-hex-5-yno-1, 4-furanose (1) with phenylacetylene, 2-propyn-1-ol or terminal acetylenic sugars gave with excellent yields the expected diynes (an enediyne when the terminal acetylene was the 3,5, 6-trideoxy-1,2-O-isopropylidene-α-D -glycero-hex-3-en-5-yno-1,4-furanose 7 ). The chloro analogue 8 of 1 on treatment with lithium thiophenate gave the corresponding phenylthio-acetylenic sugar 9 . An acetylene was also formed by reacting the gem-difluoro-olefinic sugar 10 with butyllithium whereas the same olefinic sugar and its 3-O-benzyl analogue 11 gave only a gem-fluoro-arylthio-olefinic sugar (13–15) as a mixture of the Z and E isomers (Z/E > 4) when treated with the conjugate base of an arylmercaptan.     

Enaminosucres et sucres halogénoacétyléniques. Communication préliminaire

Enamino- and Halogenoacetylenic sugars Traitment of an aldehydosugar ( 1 ) with secondary amines gave in an essentially quantitative yield the expected enamines ( 4–6 ). Chloro- and bromo-acetylenic sugars ( 11–14 ) were obtained in good yields by reacting with lithium methylphenylamide the corresponding gem-dihalo-olefinic sugars ( 7–10 ), whereas a Z-gem-fluoro-enamine ( 17 ) was formed when the difluoro-olefinic sugar 15 was submitted to the same reaction. The fluoro-enamine 17 is a useful synthetic intermediate allowing the preparation of several kinds of C-glycosylic compounds bearing heterocycles like isoxazole, chromone or coumarin.     

Préparation de dérivés de sucres acétyléniques terminaux et d'acides ynuroniques par réaction de Wittig. Note de laboratoire

Synthesis of Terminal Acetylenic Sugars Derivatives and Ynuronic Acids Derivatives by Use of a Wittig Reaction The method described for the preparation of terminal acetylenic sugars presents two advantages over earlier procedures: no new asymmetric center is created and the chain can be extended by one or more C-atoms. The method also allows preparation of ynuronic acids. The aldehydosugars derivatives 1–7 gave in good to excellent yields the corresponding gem-dibromoenoses 8–14 from which either the terminal acetylenic sugars derivatives 15–21 or the ynuronic acids 22–24 were easily prepared. A few examples of 1,3-dipolar cycloadditions (leading to 28–30 ) with these acetylenic sugar derivatives are also described.     

Utlisation d'ylides du phosphore en chimie des sucres. XIII. Synthèse de dérivés des hydroxyméthyl-3-D-glucose et-D-galactose et de composés voisins

The treatment of the 1, 2:5, 6-di-O-isopropylidene-α-D -ribo- and xylo-hexofuranos-3-uloses with cyanomethylenetriphenylphosphorane led in each case, and in almost quantitative yields, to a pair of geometrical isomers of C-cyanomethylenic sugars having respectively the ribo and the xylo configurations. Permanganate oxidation of these branched-chain unsaturated sugars afforded the corresponding gem-hydroxyformyl compounds bearing the formyl group on the more hindered face of the molecule. The formyl group of these sugars is easily derivatized to an oximino or reduced to a hydroxymethyl. The configuration at the new asymmetric carbon has been established by comparison with known compounds or by synthesis of a C(3) epimer by the classical route involving a Grignard reagent.     

gem‐Difluoroolefination of Diaryl Ketones and Enolizable Aldehydes with Difluoromethyl 2‐Pyridyl Sulfone: New Insights into the Julia–Kocienski Reaction

The direct conversion of diaryl ketones and enolizable aliphatic aldehydes into gem‐difluoroalkenes has been a long‐standing challenge in organofluorine chemistry. Herein, we report efficient strategies to tackle this problem by using difluoromethyl 2‐pyridyl sulfone as a general gem‐difluoroolefination reagent. The gem‐difluoroolefination of diaryl ketones proceeds by acid‐promoted Smiles rearrangement of the carbinol intermediate; the gem‐difluoroolefination is otherwise difficult to achieve through a conventional Julia–Kocienski olefination protocol under basic conditions due to the retro‐aldol type decomposition of the key intermediate. Efficient gem‐difluoroolefination of aliphatic aldehydes was achieved by the use of an amide base generated in situ (from CsF and tris(trimethylsilyl)amine), which diminishes the undesired enolization of aliphatic aldehydes and provides a powerful synthetic method for chemoselective gem‐difluoroolefination of multi‐carbonyl compounds. Our results provide new insights into the mechanistic understanding of the classical Julia–Kocienski reaction.     

Molecular structure and thermal stability of α-halogen-<Emphasis Type="Italic">gem</Emphasis>-dithiols

The electronic structure of α-halogen-gem-dithiols RC(SH)₂CH₂X (R = Me, Ph; X = F, Cl, Br, I) was studied by quantum chemistry methods. Four most stable rotamers were located, differing in the mutual orientation of the thiol groups and the halogen atom. The thermodynamic and kinetic characteristics of the thermolysis of α-halogen-gem-dithiols were obtained. Thermolysis of chlorine- and bromine-substituted gem-dithiols depends on the properties of the medium, namely, in aprotic media aromatic dithiols form trithianorbornane derivatives while aliphatic dithiols form thiirane derivatives. In an aqueous medium (R = Me, Ph), water promoted elimination of hydrogen sulfide with the formation of corresponding thiones is more preferable. Thermolysis of aliphatic iodine-substituted gem-dithiols proceeds as bimolecular deiodination resulting in the formation of a new C-C bond.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 559–568, March, 2005.     

Synthesis of Selectively gem-Difluorinated Molecules; Chiral gem-Difluorocyclopropanes via Chemo-Enzymatic Reaction and gem-Difluorinated Compounds via Radical Reaction

The incorporation of fluorine atoms into an organic compound can alter the chemical reactivity or biological activity of the resulting compound due to the strong electron withdrawing nature of the fluorine atom. We have synthesized many original gem-difluorinated compounds and described the results in four sections. The first section describes the synthesis of optically active-gem-difluorocyclopropanes via the chemo-enzymatic reaction; we applied these compounds to liquid crystalline molecules, then further discovered a potent DNA cleavage activity for the gem-difluorocyclopropane derivatives. The second section describes the synthesis of selectively gem-difluorinated compounds via a radical reaction; we synthesized fluorinated analogues of a sex pheromone of the male African sugarcane borer, Eldana saccharina, and used the compounds as proof for investigating the origin of pheromone molecule recognition on the receptor protein. The third involves the synthesis of 2,2-difluorinated-esters by visible light-driven radical addition of 2,2-difluoroacetate with alkenes or alkynes in the presence of an organic pigment. The last section describes the synthesis of gem-difluorinated compounds via the ring-opening of gem-difluorocyclopropanes. We further developed a novel method of synthesizing gem-difluorohomoallylic alcohols via the ring-opening of gem-difluorocyclopropane and aerobic oxidation by photo-irradiation in the presence of an organic pigment. Since gem-difluorinated compounds that were prepared by the present method have two olefinic moieties with a different reactivity at the terminal position, we accomplished the synthesis of four types of gem-difluorinated cyclic alkenols via the ring-closing-metathesis (RCM) reaction.     

金属参与的N-酰基腙的偕二氟烯丙基化反应：高效合成偕二氟高烯丙基胺

金属铟参与醛衍生的N-酰基腙 1a-1q,4a-4g与3-溴-3,3-二氟丙烯 2 的反应,分别高效得到α, α-二氟高烯丙基肼 3a-3q,5a-5g。该反应条件温和,操作简便。硝基,酚羟基,苄氧基,α, β-不饱和醛的碳-碳双键等官能团对该反应具有良好的官能团兼容性。通过用锌粉代替铟粉, 酮衍生的N-酰基腙 6a-6d 也能发生偕二氟烯丙基化反应,以中等产率得到α, α-二氟高烯丙基肼 7a-7d。裂解肼3a的 N-N键顺利得到偕二氟高烯丙基胺 8,化合物 8 经丙烯酰化,随后进行RCM关环反应,可以方便的转化为偕二氟-γ-取代α, β-不饱和内酰胺 11。     

Enhancement of Neighbouring‐Group Participation in Cu0‐Promoted Cross‐Coupling gem‐Difluoromethylenation of Aryl/Alkenyl Halides with 1,3‐Azolic Difluoromethyl Bromides

A copper(0)‐promoted direct reductive gem‐difluoromethylenation of unactivated aryl or alkenyl halides with benzo‐1,3‐azolic (oxa‐, thia‐ or aza‐) difluoromethyl bromides or 2‐bromodifluoromethyl‐1,3‐oxazoline has been developed for the construction of pharmaceutically important gem‐difluoromethylene‐linked twin molecules. The unique π‐conjugated aryl‐fused 1,3‐azolic moiety in difluoromethyl bromide substrates could stabilise the reaction intermediates, which promotes the reactivities, providing facile access to the cross‐coupling products in good to excellent yields, and allowing significant functional group tolerance. The reaction exhibits an enhanced neighbouring‐group‐participation effect. This method could provide a new strategy for the construction of gem‐difluoromethylene‐linked identical or nonidentical twin drugs through further functionalisation of 1,3‐azolic skeletons.     

4‐Ethynyl‐4‐hydroxycyclohexan‐1‐one and 4‐ethynyl‐4‐hydroxy‐2,3,5,6‐tetramethylcyclohexa‐2,5‐dien‐1‐one

The title compounds, C₈H₁₀O₂, (I), and C₁₂H₁₄O₂, (II), occurred as by‐products in the controlled synthesis of a series of bis­(gem‐alkynols), prepared as part of an extensive study of synthon formation in simple gem‐alkynol derivatives. The two 4‐(gem‐alkynol)‐1‐ones crystallize in space group P2₁/c, (I) with Z′ = 1 and (II) with Z′ = 2. Both structures are dominated by O—H?O=C hydrogen bonds, which form simple chains in the cyclo­hexane derivative, (I), and centrosymmetric dimers, of both symmetry‐independent mol­ecules, in the cyclo­hexa‐2,5‐diene, (II). These strong synthons are further stabilized by C[triple‐bond]C—H?O=C, C_methylene—H?O(H) and C_methyl—H?O(H) interactions. The direct intermolecular interactions between donors and acceptors in the gem‐alkynol group, which characterize the bis­(gem‐alkynol) analogues of (I) and (II), are not present in the ketone derivatives studied here.     

Synthesis of α,α‐Difluoromethylene Alkynes by Palladium‐Catalyzed gem‐Difluoropropargylation of Aryl and Alkenyl Boron Reagents

gem‐Difluoropropargyl bromides are versatile intermediates in organic synthesis, but have rarely been employed in transition‐metal‐catalyzed cross‐coupling reactions. The first palladium‐catalyzed gem‐difluoropropargylation of organoboron reagents with gem‐difluoropropargyl bromides is now reported. The reaction proceeds under mild reaction conditions with high regioselectivity; it features a broad substrate scope and excellent functional‐group compatibility and thus provides an attractive approach for the synthesis of complex fluorinated molecules, in particular for drug discovery and development.     

Divergent Mechanistic Routes for the Formation of gem‐Dimethyl Groups in the Biosynthesis of Complex Polyketides

The gem‐dimethyl groups in polyketide‐derived natural products add steric bulk and, accordingly, lend increased stability to medicinal compounds, however, our ability to rationally incorporate this functional group in modified natural products is limited. In order to characterize the mechanism of gem‐dimethyl group formation, with a goal toward engineering of novel compounds containing this moiety, the gem‐dimethyl group producing polyketide synthase (PKS) modules of yersiniabactin and epothilone were characterized using mass spectrometry. The work demonstrated, contrary to the canonical understanding of reaction order in PKSs, that methylation can precede condensation in gem‐dimethyl group producing PKS modules. Experiments showed that both PKSs are able to use dimethylmalonyl acyl carrier protein (ACP) as an extender unit. Interestingly, for epothilone module 8, use of dimethylmalonyl‐ACP appeared to be the sole route to form a gem‐dimethylated product, while the yersiniabactin PKS could methylate before or after ketosynthase condensation.     

Why is benzyl‐gem‐diacetate remarkably stable in aqueous solution?

Benzyl‐gem‐diacetate is synthesized and performed its solvolysis in water at 25°C. It did not solvolize even for a year, whereas its counterparts benzyl‐gem‐diazide and dihalides underwent spontaneous cleavage through a S_N1 mechanism in aqueous solution to give benzaldehydes as the final product through α‐azido benzyl and α‐halo benzyl carbocation intermediates, respectively. The possible explanations are offered for the extraordinary stability of the benzyl‐gem‐diacetate in water. © 2009 Wiley Periodicals, Inc. Int J Chem Kinet 41: 554–557, 2009     

Rhodium-Catalyzed Regio- and Diastereoselective [3+2] Cycloaddition of gem-Difluorinated Cyclopropanes with Internal Olefins

Direct synthesis of gem-difluorinated carbocyclic molecules represents a longstanding challenge in organic chemistry. Herein, a Rh-catalyzed [3+2] cycloaddition reaction between readily available gem-difluorinated cyclopropanes (gem-DFCPs) and internal olefins has been developed, enabling the efficient synthesis of gem-difluorinated cyclopentanes with good functional group compatibility, excellent regioselectivity and good diastereoselectivity. The resulting gem-difluorinated products can undergo downstream transformations to access various mono-fluorinated cyclopentenes and cyclopentanes. This reaction demonstrates the use of gem-DFCPs as a type of “CF₂” C3 synthon for cycloaddition under transition metal catalysis, which provides potential strategy for synthesizing other gem-difluorinated carbocyclic molecules.     

Sur la Similitude des Déformations du Noyau Cyclohexanonique Induites par les Groupes Tertiobutyle et gem-Diméthyle

X-ray and NMR (250 MHz) data for chlorinated 4,4-dimethylcyclohexanones lead to the following conclusions: carbonyl and chlorine substituent effects on ²J and ³J coupling constants are similar to those observed for 4-tert-butylcyclohexanones. In other respects, the gem dimethyl and the tert-butyl groups induce on the ring similar large ⁴J coupling constants (H-3′? C-3? C-4? C-5? H-5′); the results can be interpreted in terms of local gemoetric deformations and additivity of these deformations. The determination of dihedral angles by Lambert's method and from X-ray data shows the identity of the structures in the solid state and the dissolved state and confirms the great structural similarity between 4-tert-butyl- and 4,4-dimethylcyclohexanone derivatives.