Thiourea-catalysed conjugate additions of amines to vinyl phosphonates and phosphinates.

Thiourea catalysts activated α,ß-unsaturated phosphonates and phosphinates toward conjugate addition by amines to give ß-aminophosphonates and ß-aminophosphinates. The organocatalytic methodology was used to synthesise 15 ß-aminophosphonates and -phosphinates in yields up to 99%. A gram-scale example furnished the corresponding ß-aminophosphonate in an isolated yield of 99% with 97% catalyst recovery. Based on mechanistic experiments, hydrogen bonding between the phosphoryl oxygen and thiourea are proposed to play a crucial role in substrate activation.

Non-photopic and photopic visual cycles differentially regulate immediate, early, and late phases of cone photoreceptor-mediated vision.

Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Müller glia. In the RPE, isomerization of all-trans-retinyl esters to 11-cis-retinol is mediated by the retinoid isomerohydrolase Rpe65. A putative alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Müller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early, and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, while the emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaptation displayed significantly attenuated immediate photopic vision concomitant with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 min of light, early photopic vision was recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde supplementation. Genetic knockout of Des1 (degs1) or retinaldehyde-binding protein 1b (rlbp1b) did not eliminate photopic vision in zebrafish. Our findings define molecular and temporal requirements of the nonphotopic or photopic visual cycles for mediating vision in bright light.

Site-Selective Acylation of Pyranosides with Oligopeptide Catalysts.

Herein, we report the oligopeptide-catalyzed site-selective acylation of partially protected monosaccharides. We identified catalysts that invert site-selectivity compared to N-methylimidazole, which was used to determine the intrinsic reactivity, for 4,6-O-protected glucopyranosides (trans-diols) as well as 4,6-O-protected mannopyranosides (cis-diols). The reaction yields up to 81% of the inherently unfavored 2-O-acetylated products with selectivities up to 15:1 using mild reaction conditions. We also determined the influence of protecting groups on the reaction and demonstrate that our protocol is suitable for one-pot reactions with multiple consecutive protection steps.

Synthesis of glycosyl chlorides using catalytic Appel conditions.

The stereoselective synthesis of glycosyl chlorides using catalytic Appel conditions is described. Good yields of α-glycosyl chlorides were obtained using a range of glycosyl hemiacetals, oxalyl chloride and 5 mol% Ph3PO. For 2-deoxysugars treatment of the corresponding hemiacetals with oxalyl chloride without phosphine oxide catalyst also gave good yields of glycosyl chloride. The method is operationaly simple and the 5 mol% phosphine oxide by-product can be removed easily. Alternatively a one-pot, multi-catalyst glycosylation can be carried out to transform the glycosyl hemiacetal directly to a glycoside.

Benzylation Reactions in DMF Lead to an Impurity Which Acts as an Organocatalyst Poison in Thiourea-Catalyzed Glycosylations.

The benzylation of alcohols with the commonly used combination of benzyl bromide and sodium hydride in DMF can lead to the formation of an amine side product, N,N'-dimethyl-1-phenyl-1-(o-tolyl)methanamine. This amine coeluted with benzylated galactal during column chromatography and was found to be a catalyst poison in thiourea-catalyzed glycosylations of galactals. It may also be problematic for other base-sensitive reactions involving benzylated substrates. Solutions to this problem are described.

Synthesis of α-substituted vinylsulfonium salts and their application as annulation reagents in the formation of epoxide- and cyclopropane-fused heterocycles.

The discovery of new methods for the synthesis of classes of potentially bioactive molecules remains an important goal for synthetic chemists. Vinylsulfonium salts have been used for the synthesis of a wide variety of small heterocyclic motifs; however, further developments to this important class of reagents has been focused on reaction with new substrates rather than development of new vinylsulfonium salts. We herein report the synthesis of a range of α-substituted vinylsulfonium tetraphenylborates (10 examples) in a 3 step procedure from commercially available styrenes. The important role of the tetraphenylborate counterion on the stability and accessibility of the vinylsulfonium salts is also detailed. The α-substituted vinylsulfonium tetraphenylborates gave good to excellent yields in the epoxyannulation of ß-amino ketones (15 examples) and the cyclopropanation of allylic amines (4 examples). Hydrogenation of an epoxyannulation product proceeded with good diastereoselectivity.

A 3,4-trans-fused cyclic protecting group facilitates α-selective catalytic synthesis of 2-deoxyglycosides.

A practical approach has been developed to convert glucals and rhamnals into disaccharides or glycoconjugates with high α-selectivity and yields (77-97%) using a trans-fused cyclic 3,4-O-disiloxane protecting group and TsOH⋅H2O (1 mol%) as a catalyst. Control of the anomeric selectivity arises from conformational locking of the intermediate oxacarbenium cation. Glucals outperform rhamnals because the C6 side-chain conformation augments the selectivity.

Practical and highly selective sulfur ylide-mediated asymmetric epoxidations and aziridinations using a cheap and readily available chiral sulfide: extensive studies to map out scope, limitations, and rationalization of diastereo- and enantioselectivities.

The chiral sulfide, isothiocineole, has been synthesized in one step from elemental sulfur, γ-terpinene, and limonene in 61% yield. A mechanism involving radical intermediates for this reaction is proposed based on experimental evidence. The application of isothiocineole to the asymmetric epoxidation of aldehydes and the aziridination of imines is described. Excellent enantioselectivities and diastereoselectivities have been obtained over a wide range of aromatic, aliphatic, and α,ß-unsaturated aldehydes using simple protocols. In aziridinations, excellent enantioselectivities and good diastereoselectivities were obtained for a wide range of imines. Mechanistic models have been put forward to rationalize the high selectivities observed, which should enable the sulfide to be used with confidence in synthesis. In epoxidations, the degree of reversibility in betaine formation dominates both the diastereoselectivity and the enantioselectivity. Appropriate tuning of reaction conditions based on understanding the reaction mechanism enables high selectivities to be obtained in most cases. In aziridinations, betaine formation is nonreversible with semistabilized ylides and diastereoselectivities are determined in the betaine forming step and are more variable as a result.

Iodine-mediated photoinduced tuneable disulfonylation and sulfinylsulfonylation of alkynes with sodium arylsulfinates.

An efficient transition-metal free iodine-mediated tuneable disulfonylation and sulfinylsulfonylation of alkynes with sodium arylsulfinates under visible light irradiation has been developed. This photochemical protocol offers broad substrate scope of 1,2-bissulfonylethenes with high functional group tolerance and good yields under mild reaction conditions. In addition, it was found that ß-sulfinyl alkenylsulfones can be obtained in the absence of base. It is proposed that the reactions proceed via sulfonyl and sulfinyl radicals.

Visible-light-induced bifunctionalisation of (homo)propargylic amines with CO2 and arylsulfinates.

An unprecedented carboxylative sulfonylation of (homo)propargyl amines with CO2 and sodium arylsulfinates under visible light irradiation has been developed with high efficiency. This ruthenium-catalysed photochemical protocol offers broad substrate scope giving 2-oxazolidinones and 2-oxazinones bearing alkyl sulfones in good yields under ambient reaction conditions. An in situ double bond isomerisation occurs in tandem. A mechanistic rationale for these radical-initiated carboxylative cyclisations involving sulfinyl radicals is presented, supported by control and quenching experiments.

Accessing unsymmetrical Ru(II) bipyridine complexes: a versatile synthetic mechanism for fine tuning photophysical properties.

Three novel unsymmetrical Ru(II) bipyridine complexes were generated via a convenient, modular, convergent synthetic route. An investigation of their photophysical properties revealed solvent-dependent excited state behaviour including altered absorption and emission wavelengths, emission lifetimes and quantum yields of phosphorescence.

α-Selective organocatalytic synthesis of 2-deoxygalactosides.

Alpha rules: A thiourea acts as an efficient organocatalyst for the glycosylation of protected galactals to form oligosaccharides containing a 2-deoxymonosaccharide moiety. The reaction is highly stereoselective for α-linkages and proceeds by way of a syn-addition mechanism.

Stereoselective ß-mannosylations and ß-rhamnosylations from glycosyl hemiacetals mediated by lithium iodide.

Stereoselective ß-mannosylation is one of the most challenging problems in the synthesis of oligosaccharides. Herein, a highly selective synthesis of ß-mannosides and ß-rhamnosides from glycosyl hemi-acetals is reported, following a one-pot chlorination, iodination, glycosylation sequence employing cheap oxalyl chloride, phosphine oxide and LiI. The present protocol works excellently with a wide range of glycosyl acceptors and with armed glycosyl donors. The method doesn't require conformationally restricted donors or directing groups; it is proposed that the high ß-selectivities observed are achieved via an SN2-type reaction of α-glycosyl iodide promoted by lithium iodide.

Synthesis of Bis-heteroaryls Using Grignard Reagents and Pyridylsulfonium Salts.

Herein are reported ligand-coupling reactions of Grignard reagents with pyridylsulfonium salts. The method has wide functional group tolerance and enables the formation of bis-heterocycle linkages, including 2,4'-, 2,3'-, and 2,2'-bipyridines, as well as pyridines linked to pyrimidines, pyrazines, isoxazoles, and benzothiophenes. The methodology was successfully applied to the synthesis of the natural products caerulomycin A and E.

Practical and highly selective sulfur ylide mediated asymmetric epoxidations and aziridinations using an inexpensive, readily available chiral sulfide. Applications to the synthesis of quinine and quinidine.

Heating one of the most abundant naturally occurring inorganic chemicals (elemental sulfur) with one of the most readily available homochiral molecules (limonene) gives a one-step synthesis of a chiral sulfide which exhibits outstanding selectivities in sulfur ylide mediated asymmetric epoxidations and aziridinations. In particular reactions of benzyl and allylic sulfonium salts with both aromatic and aliphatic aldehydes gave epoxides with perfect enantioselectivities and the highest diastereoselectivities reported to date. In addition reactions with imines gave aziridines again with the highest enantioselectivities and diastereoselectivities reported to date. The reactions are scaleable, and the sulfide can be reisolated in high yield. The epoxidation has been used as the key step in a convergent and stereoselective synthesis of each of the diastereoisomers of the cinchona alkaloids, quinine and quinidine.

On the mechanism of ylide-mediated cyclopropanations: evidence for a proton-transfer step and its effect on stereoselectivity.

In this paper, we describe studies on the cyclopropanation of Michael acceptors with chiral sulfur ylides. It had previously been found that semi-stabilized sulfonium ylides (e.g., Ph-stabilized) reacted with cyclic and acyclic enones and substituted acrylates with high ee and that stabilized sulfonium ylides (e.g., ester-stabilized) reacted with cyclic enones again with high ee. The current study has focused on the reactions of stabilized sulfonium ylides with acyclic enones which unexpectedly gave low ee. Furthermore, a clear correlation of ee with ylide stability was observed in reactions with methyl vinyl ketone (MVK): ketone-stabilized ylide gave 25% ee, ester-stabilized ylide gave 46% ee, and amide-stabilized ylide gave 89% ee. It is believed that following betaine formation an unusual proton transfer step intervenes which compromises the enantioselectivity of the process. Thus, following addition of a stabilized ylide to the Michael acceptor, rapid and reversible intramolecular proton transfer within the betaine intermediate, prior to ring closure, results in an erosion of ee. Proton transfer occurred to the greatest extent with the most stabilized ylide (ketone). When the same reactions were carried out with deuterium-labeled sulfonium ylides, higher ee's were observed in all cases since proton/deuteron transfer was slowed down. The competing proton transfer or direct ring-closure pathways that are open to the betaine intermediate apply not only to all sulfur ylides but potentially to all ylides. By applying this model to S-, N-, and P-ylides we have been able to rationalize the outcome of different ylide reactions bearing a variety of substituents in terms of chemo- and enantioselectivity.

Synthesis of Pyridylsulfonium Salts and Their Application in the Formation of Functionalized Bipyridines.

An S-selective arylation of pyridylsulfides with good functional group tolerance was developed. To demonstrate synthetic utility, the resulting pyridylsulfonium salts were used in a scalable transition-metal-free coupling protocol, yielding functionalized bipyridines with extensive functional group tolerance. This modular methodology permits selective introduction of functional groups from commercially available pyridyl halides, furnishing symmetrical and unsymmetrical 2,2'- and 2,3'-bipyridines. Iterative application of the methodology enabled the synthesis of a functionalized terpyridine with three different pyridine components.

Stereoselective Glycosylation of 2-Nitrogalactals Catalyzed by a Bifunctional Organocatalyst.

The use of a bifunctional cinchona/thiourea organocatalyst for the direct and α-stereoselective glycosylation of 2-nitrogalactals is demonstrated for the first time. The conditions are mild, practical, and applicable to a wide range of glycoside acceptors with products being isolated in good to excellent yields. The method is exemplified in the synthesis of mucin type Core 6 and 7 glycopeptides.

Synthesis of 6- and 7-Membered N-Heterocycles Using α-Phenylvinylsulfonium Salts.

A concise synthesis of stereodefined C-substituted morpholines, piperazines, azepines, and oxazepines in moderate to excellent yields (27% to 75%) is reported by reaction of 1,2- or 1,3-amino alcohol/1,2- or 1,3-diamine with an α-phenylvinylsulfonium salt. High levels of regio- and diastereoselectivity (from 2:1 to >20:1) are observed through judicious choice of base (Cs2CO3) and solvent (CH2Cl2). Reactions are performed at ambient temperature and open to air and do not require anhydrous solvent. The deprotection of the N-sulfonamide protecting groups (N-Ts and N-Ns) is also demonstrated. Factors affecting regio- and diastereocontrol are discussed.