Eoghan M. McGarrigle

An Annulation Reaction for the Synthesis of Morpholines, Thiomorpholines, and Piperazines from β‐Heteroatom Amino Compounds and Vinyl Sulfonium Salts

The nitrogen-containing heterocycles comprising morpholines, thiomorpholines, and piperazines are some of the most important pharmacophores in medicinal chemistry. However, the direct synthesis of such compounds by alkylation of b-amino alcohols/thiols/amines with 1,2-dihalo derivatives is often fraught with low yields and side reactions. 1,2Dihalogen derivatives are generally poor electrophiles and reactions are often accompanied by competing elimination processes. A solution to this problem is to carry out a threestep sequence employing an a-halogen acid halide as the electrophile. Following amide formation and intramolecular alkylation, reduction finally furnishes the required heterocycles. Herein, we describe the application of a novel concept to prepare these pharmacologically important heterocycles from b-amino alcohols/thiols/amines in one step and high yield. We reasoned that soft electrophiles operating under less basic conditions would minimize competing elimination pathways and therefore considered the possibility of employing Michael acceptors. This led us to vinyl onium salts (e.g., 1). We expected that, following conjugate addition of one of the heteroatoms, an ylide 4 would be generated that could undergo proton transfer with the other heteroatom (Scheme 1). The heteroatom anion generated, 5, would then attack the onium ion electrophile to effect ring-closure and produce the required heterocycle. Although vinyl onium salts have been employed in three-component coupling reactions with nucleophiles and electrophiles, their potential to react according to the pathway shown in Scheme 1 has not previously been recognized. Of the readily available vinyl onium salts, it was thought that sulfonium and phosphonium would be better at promoting the conjugate addition step than ammonium since the ylide intermediate is better stabilized. However, to promote cyclization leaving group ability of the onium is critical and this falls in the order S>N @ P. These considerations led us to examine vinyl sulfonium salts, and in particular diphenyl vinyl sulfonium salt 1. This salt was easily prepared through a modified procedure as shown in Scheme 2. In this

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.

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.

Bromoethylsulfonium salt--a more effective annulation agent for the synthesis of 6- and 7-membered 1,4-heterocyclic compounds.

Reaction of bromoethylsulfonium salt with 1,2-/1,3-aminoalcohols gave six- and seven-membered rings in good-to-excellent yields. The reactions proceed through generation of a vinyl sulfonium salt followed by annulation to give 1,4-heterocyclic compounds such as morpholines and benzoxazepines in a simple procedure. The method accommodates a range of nitrogen substituents and the amino alcohol can be substituted by amino thiols and diamines to give thiomorpholines, piperazines and benzodiazepines.

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 ees 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.

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,β-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.

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.

An Efficient Synthesis of Imidazolinium Salts Using Vinyl Sulfonium Salts

The synthesis of imidazolinium salts from the reaction of formamidines and (2-bromoethyl)diphenylsulfonium triflate is described. A variety of symmetrical and unsymmetrical imidazolinium triflate salts were synthesized in high yield in short reaction times under mild conditions. Aromatic and aliphatic N-substituents work well. The reaction is proposed to proceed via generation of a vinyl sulfonium salt intermediate from the bromoethylsulfonium triflate.

Diastereoselective synthesis of CF3-substituted, epoxide-fused heterocycles with β-(trifluoromethyl)vinylsulfonium salts.

CF(3)-substituted vinyl diphenylsulfonium triflate is an effective annulation reagent for the formation of α-CF(3) substituted, epoxide-fused heterocycles (pyrrolidines, piperidines, and tetrahydrofurans). This simple method affords a variety of valuable heterocyclic building blocks in a highly diastereoselective manner (dr >20:1).

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.