Amine-linked diglycosides: Synthesis facilitated by the enhanced reactivity of allylic electrophiles, and glycosidase inhibition assays

• Ian Cumpstey,
• Jens Frigell,
• Elias Pershagen,
• Tashfeen Akhtar,
• Elena Moreno-Clavijo,
• Inmaculada Robina,
• Dominic S. Alonzi and
• Terry D. Butters

Beilstein J. Org. Chem. 2011, 7, 1115–1123, doi:10.3762/bjoc.7.128

• methods (COSY, HSQC) gave an unambiguous indication that, in all cases, the nitrogen nucleophile had attacked C-4, as judged by an upfield shifted 13C signal, and that the unsaturated bond was between C-2 and C-3. Hence these reactions proceeded with essentially complete regioselectivity, with no SN2

• single diastereomer. This is consistent with an SN2 pathway with inversion of configuration, which is as expected for Mitsunobu reactions. The same was true of the other sulfonamide nucleophiles, 7 and 9. Moreover, the erythro configuration of coupling product 15 was proved by the large value of the J4,5

• pseudodisaccharides. Triflamides and nosylamides were similarly effective as nucleophiles in Mitsunobu coupling reactions with allylic alcohols. The Mitsunobu coupling reactions proceeded with inversion of configuration, and SN2’ type reactions with C=C double bond migration were not observed. A palladium catalysed

Toward an integrated route to the vernonia allenes and related sesquiterpenoids

• Da Xu,
• Michael A. Drahl and
• Lawrence J. Williams

Beilstein J. Org. Chem. 2011, 7, 937–943, doi:10.3762/bjoc.7.104

• no computational mechanistic study on these reactions has appeared as a guide in this regard. Admittedly, there are distinct differences between fragmentation and substitution; nevertheless, by analogy to SN2 reactions, C–C fragmentation substrates with angles significantly less than 180° may fail

When gold can do what iodine cannot do: A critical comparison

• Sara Hummel and
• Stefan F. Kirsch

Beilstein J. Org. Chem. 2011, 7, 847–859, doi:10.3762/bjoc.7.97

• reaction does not occur via electrophilic activation. Instead, due to the iodide ion still present in the reaction mixture, the ammonium ion intermediate undergoes SN1 or SN2 substitution, or even E2 elimination of an alkyl group. This system yields products in up to quantitative yields, and successfully

A comparative study of the Au-catalyzed cyclization of hydroxy-substituted allylic alcohols and ethers

• Berenger Biannic,
• Thomas Ghebreghiorgis and
• Aaron Aponick

Beilstein J. Org. Chem. 2011, 7, 802–807, doi:10.3762/bjoc.7.91

• corresponding ethers. Additionally, it is reported that Reaxa QuadraPureTM MPA is an efficient scavenging reagent that halts the reaction progress. Keywords: allylic alcohol; allylic ether; Au-catalyzed; SN2'; tetrahydropyran; Introduction Saturated oxygen heterocycles are found in a wide variety of

• from our laboratory and others have demonstrated that unsaturated alcohols, such as allylic and propargylic alcohols, are reactive substrates that readily participate in dehydrative formal SN2' reactions [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. The formation of tetrahydropyrans is

• more synthetically useful substrates. Conclusion In conclusion, it has been demonstrated that a variety of allylic ethers undergo Au-catalyzed formal SN2' reactions to form tetrahydropyrans. The reaction of allylic alcohols appears to be faster, although the leaving group is traditionally not

Alkene selenenylation: A comprehensive analysis of relative reactivities, stereochemistry and asymmetric induction, and their comparisons with sulfenylation

• Vadim A. Soloshonok and
• Donna J. Nelson

Beilstein J. Org. Chem. 2011, 7, 744–758, doi:10.3762/bjoc.7.85

• ]. It is well established that the rate determining step in benzenesulfenyl chloride addition is the formation of thiiranium intermediate; specifically the alkene π electrons displace Cl− in an SN2 reaction to give the thiiranium ion [89]. On the other hand, recent studies ruled out the formation of the

Complete transfer of chirality in an intramolecular, thermal [2 + 2] cycloaddition of allene-ynes to form non-racemic spirooxindoles

• Kay M. Brummond and
• Joshua M. Osbourn

Beilstein J. Org. Chem. 2011, 7, 601–605, doi:10.3762/bjoc.7.70

• propargyl acetate 7 to an enantiomerically enriched allene 8. It has been previously shown that delivery of an alkyl group from an organocuprate in an SN2’ fashion occurs with retention of chiral information in the resulting allene [9]; thus we began by screening cuprate conditions to form the desired

Gold-catalyzed regioselective oxidation of terminal allenes: formation of α-methanesulfonyloxy methyl ketones

• Yingdong Luo,
• Guozhu Zhang,
• Erik S. Hwang,
• Thomas A. Wilcoxon and
• Liming Zhang

Beilstein J. Org. Chem. 2011, 7, 596–600, doi:10.3762/bjoc.7.69

• be formed. While C may revert back to the allene substrate, we suspect that a SN2'-type reaction by an external nucleophile could facilitate the fragmentation of the O–Y bond, ultimately leading to useful products via intermediate D. Herein we report our preliminary studies, which led to a facile

• undergo protonation to form intermediate F with MsO− as the counter anion. An SN2'-type substitution by the anion would afford the observed product. This substitution is facilitated by the fragmentation of the weak N–O bond and the annihilation of the charges. Conclusion We have successfully realized the

Asymmetric synthesis of tertiary thiols and thioethers

• Jonathan Clayden and
• Paul MacLellan

Beilstein J. Org. Chem. 2011, 7, 582–595, doi:10.3762/bjoc.7.68

• (C–S bond formation). Alternatively, stereoselective alkylation, arylation or acylation of a secondary sulfur-based substrate could generate the quaternary centre (C–C bond formation). Review 1 Carbon–sulfur bond formation 1.1 SN2 displacement of a leaving group Stereospecific nucleophilic attack on

• substituted carbon atoms is a simple and versatile way to construct stereocentres next to heteroatoms with overall inversion of stereochemistry. Sulfur nucleophiles are commonly used very effectively to accomplish reactions of this type [9]. However, SN2 displacements are very sensitive to steric crowding at

• the reaction centre: SN1 substitution and elimination reactions are almost always favoured over the SN2 pathway in quaternary electrophiles, limiting the use of SN2 reactions for the synthesis of tertiary thiols. 1.1.1 Sulfonate leaving groups The efficiency of sulfonates as leaving groups has allowed

Kinetic evaluation of the solvolysis of isobutyl chloro- and chlorothioformate esters

• Malcolm J. D’Souza,
• Matthew J. McAneny,
• Dennis N. Kevill,
• Jin Burm Kyong and
• Song Hee Choi

Beilstein J. Org. Chem. 2011, 7, 543–552, doi:10.3762/bjoc.7.62

• studies by other groups favored competing SN1 and SN2 pathways for the alkyl chloro-, chlorothio-, chlorothiono-, and dithiochloroformates [50][51][52][53][54][55][56][57][58][59]. Upon evaluating the rates of hydrolysis in aqueous solvents, Queen [54][55] suggested that with increasing electron donation

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

Palladium-catalyzed formation of oxazolidinones from biscarbamates: a mechanistic study

• Benan Kilbas and
• Metin Balci

Beilstein J. Org. Chem. 2011, 7, 246–253, doi:10.3762/bjoc.7.33

• SN2' substitution reaction mechanism [27][28][29][30], nucleophiles attack the double bond from the same side from which the leaving group departs, as shown below (Figure 3). Therefore, we assume that metal is bonded to the allylic system from the same side as the nucleophile attacking the double bond

Carbasugar analogues of galactofuranosides: α-O-linked derivatives

• Jens Frigell and
• Ian Cumpstey

Beilstein J. Org. Chem. 2010, 6, 1127–1131, doi:10.3762/bjoc.6.129

• the transition state is approached also under neutral or base-catalysed conditions [14]. Carbon C2 bears a β electron-withdrawing group (the C3 benzyl ether), whereas C1 does not. Hence, from an electronic point of view, SN2 reactions should be more favourable at C1 than at C2. The same concept is a

• major factor in explaining the generally low reactivity of carbohydrates (at non-anomeric positions) in SN2 reactions. Carbapyranose 1,2-epoxides with α-gluco 3 and α-galacto configurations did not give such good results. With amine nucleophiles, attack was often unregioselective [15]: attack at C1

• , our best results were obtained using an oxidation–reduction approach. Attempted SN2 reactions (Mitsunobu reaction or sulfonate displacement) gave inferior results. Hence the C2 alcohols 8 and 11 were oxidised under Swern conditions to give the ketones 15 and 16. Reduction of ketone group in ethyl

β-Hydroxy carbocation intermediates in solvolyses of di- and tetra-hydronaphthalene substrates

• Jaya S. Kudavalli and
• Rory A. More O'Ferrall

Beilstein J. Org. Chem. 2010, 6, 1035–1042, doi:10.3762/bjoc.6.118

• . The normal salt effect exerted by the sodium azide also confirms that the solvolysis proceeds via the formation of a carbocation intermediate rather than by an SN2 mechanism. 1-Chloro- and 1-chloro-2-hydroxy-1,2-tetrahydronaphthalenes Rate constants for solvolysis of cis- and trans-1-chloro-2-hydroxy

Catalysis: transition-state molecular recognition?

• Ian H. Williams

Beilstein J. Org. Chem. 2010, 6, 1026–1034, doi:10.3762/bjoc.6.117

• concept. It is shown that reactant binding is intrinsically inhibitory, and that attempts to design catalysts that focus simply upon attractive interactions in a binding site may fail. Free-energy changes along the reaction coordinate for SN2 methyl transfer catalysed by the enzyme catechol-O-methyl

• reduction in barrier height by means of differential stabilisation. The cases discussed below all exemplify TS molecular recognition and stabilisation relative to the reactant state. Catalyst design: preferential TS binding Methyl group transfer from an electrophile to a nucleophile by an SN2 mechanism is

• -methyldibenzothiophenium ion at 25 °C in methanol [12]. According to the orthodox view, Schowen and co-workers interpreted these observations in terms of a tighter SN2 transition state for the COMT-catalysed reaction than for the non-enzymic reaction, and consequently proposed the “compression hypothesis” for enzymic

Redox-active tetrathiafulvalene and dithiolene compounds derived from allylic 1,4-diol rearrangement products of disubstituted 1,3-dithiole derivatives

• Filipe Vilela,
• Peter J. Skabara,
• Christopher R. Mason,
• Thomas D. J. Westgate,
• Asun Luquin,
• Simon J. Coles and
• Michael B. Hursthouse

Beilstein J. Org. Chem. 2010, 6, 1002–1014, doi:10.3762/bjoc.6.113

• by two SN2 reactions with 1,2-dibromoethane in THF to yield 27(56% yield) after purification by column chromatography (eluting with 1:1 (v/v) CH2Cl2:petroleum ether). Dithiolate 24 was also generated from the analogous reaction with 3. On this occasion, treatment of 24 with excess nickel(II)chloride

Kinetic studies and predictions on the hydrolysis and aminolysis of esters of 2-S-phosphorylacetates

• Milena Trmčić and
• David R. W. Hodgson

Beilstein J. Org. Chem. 2010, 6, 732–741, doi:10.3762/bjoc.6.87

• also give rise to p- and m-nitrophenolate ions during their hydrolyses. High concentrations of both thiophosphate 4 and 2-bromoacetic acid esters 1 (R = pNP) and 1 (R = mNP) were used in order to ensure that the SN2 reactions between these reagents occurred rapidly with minimal scope for hydrolysis of

Shelf-stable electrophilic trifluoromethylating reagents: A brief historical perspective

• Norio Shibata,
• Andrej Matsnev and
• Dominique Cahard

Beilstein J. Org. Chem. 2010, 6, No. 65, doi:10.3762/bjoc.6.65

• studies with appropriate analytical tools should be conducted in order to obtain more insight on the transfer of the electrophilic CF3 group. A bimolecular nucleophilic substitution, SN2 type mechanism, is often suggested, although a single electron transfer mechanism cannot be ruled out depending on the

(Pseudo)amide-linked oligosaccharide mimetics: molecular recognition and supramolecular properties

• José L. Jiménez Blanco,
• Fernando Ortega-Caballero,
• Carmen Ortiz Mellet and
• José M. García Fernández

Beilstein J. Org. Chem. 2010, 6, No. 20, doi:10.3762/bjoc.6.20

• , Chiara and co-workers have described a novel complementary approach in which the oxazoline ring is generated by SN2 nucleophilic displacement reaction from the β-hydroxyurea 30 via the triflate intermediate 31 (Scheme 3) [65]. A similar methodology was used by the same authors to prepare the trehazolin

Diastereoselective functionalisation of benzo-annulated bicyclic sultams: Application for the synthesis of cis-2,4-diarylpyrrolidines

• Susan Kelleher,
• Pierre-Yves Quesne and
• Paul Evans

Beilstein J. Org. Chem. 2009, 5, No. 69, doi:10.3762/bjoc.5.69

• demonstrates the pronounced fold of this structure. Consequently, since the SN2 process is retarded the bromide may then intercept either carbocation 21, or 22 in an SN1 sense, from the less hindered, top face, forming 13a and 13b. Using methanol as the solvent the cis-1,2-difunctionalised compounds 16a and

Iridium-catalyzed asymmetric ring-opening reactions of oxabicyclic alkenes with secondary amine nucleophiles

• Dingqiao Yang,
• Ping Hu,
• Yuhua Long,
• Yujuan Wu,
• Heping Zeng,
• Hui Wang and
• Xiongjun Zuo

Beilstein J. Org. Chem. 2009, 5, No. 53, doi:10.3762/bjoc.5.53

• 1a are then reversibly coordinated to the iridium center of the catalyst to give the intermediate C. Oxidative insertion of C in to the C–O bond forms D. Then, attack of the secondary amine nucleophile along with configurational inversion is proposed to occur in an SN2′ displacement of the iridium

Mitomycins syntheses: a recent update

• Jean-Christophe Andrez

Beilstein J. Org. Chem. 2009, 5, No. 33, doi:10.3762/bjoc.5.33

• the planned construction of the aziridine by tandem SN2 displacement. Exploiting the facial selectivity of compound 38, the direct introduction of an aziridine equivalent was attempted by 1,3-dipolar cycloaddition of an alkyl azide. As Frank noted, cycloaddition of azides to 3H-pyrrolo [1,2-a]indoles

• cyclisation of an aziridinyl radical (Scheme 27) [89]. This approach allowed stereocontrolled, rapid access to either enantiomer of this type of structure. Compound 94 was obtained by SN2 displacement with chiral aziridinyl triflate 100 followed by decarboxylation. Among the numerous routes to synthesize

• give 166. Reduction of the azide with trimethylphosphite followed by intramolecular SN2 displacement gave aziridine 167. Due to the reactivity of the aziridine in mitomycin C, a special protecting group was used during the synthesis. The aziridine protecting phosphate group in 167 was cleaved using

Oxidative cyclization of alkenols with Oxone using a miniflow reactor

• Yoichi M. A. Yamada,
• Kaoru Torii and
• Yasuhiro Uozumi

Beilstein J. Org. Chem. 2009, 5, No. 18, doi:10.3762/bjoc.5.18

• subsequent oxirane ring opening with the intramolecular oxygen nucleophile (an intramolecular SN2 reaction) to afford the product 2 stereospecifically [44][45]. It should be noted that the miniflow cyclization of 1a was continuously carried out to give a quantitative conversion of 2a over 2 h. Conclusion In

Efficient 1,4-addition of α-substituted fluoro(phenylsulfonyl)methane derivatives to α,β-unsaturated compounds

• G. K. Surya Prakash,
• Xiaoming Zhao,
• Sujith Chacko,
• Fang Wang,
• Habiba Vaghoo and
• George A. Olah

Beilstein J. Org. Chem. 2008, 4, No. 17, doi:10.3762/bjoc.4.17

• of PMe3 to alkene 4 generates the dipolar intermediate. The latter abstracts a proton from the α-fluoro-substituted methylene derivative 3, followed by an intermolecular SN2 reaction to furnish the desired product 5 and the release of PMe3 (Scheme 1). The mechanism supports the fact that the less