Johnathan V. Matlock

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.

Efficient Synthesis of Cyclopropane‐Fused Heterocycles with Bromoethylsulfonium Salt

Sven P. Fritz, Johnathan V. Matlock, Eoghan M. McGarrigle,* and Varinder K. Aggarwal* The 3-azabicycloACHTUNGTRENNUNG[3.1.0]hexane is a common motif in natural products. Furthermore this rigid framework represents a privileged class of pharmacologically active compounds, often showing enhanced binding affinities with their targets (Figure 1). These bicycles also represent conformationally restricted analogues of piperidines (e.g. trovafloxacin). When substituted with a carboxylic acid moiety, they resemble conformationally restricted analogues of glutamate, gamma-amino butyric acid (GABA) or a/b-proline analogues (Figure 2). Numerous methods have been developed for the construction of azabicyclo ACHTUNGTRENNUNG[3.1.0]hexanes.[10] These include the Kulinkovich/de Meijere reaction, 12] cyclisation of tethered amines with metals (Pd, Ru, Rh, Ag), cyclisation of tethered cyclopropanes and the Simmons–Smith/ Corey–Chaykovsky/sulfur ylide–Au cyclopropanations. These methods are usually only effective in the synthesis of one specific type of scaffold. We were keen to develop a general strategy that could deliver 3-azabicycloACHTUNGTRENNUNG[3.1.0]hexanes with a range of functional groups in a range of positions. Our design plan for the synthesis of the scaffold was to effect a tandem process initiated by conjugate addition of an unsaturated amine 1 to vinyl sulfonium salt 2, generated in situ from the stable and crystalline salt 3 (Scheme 1). The intermediate sulfur ylide 4 would undergo intramolecular addition to the Michael acceptor to give a sulfonium enolate 5, which would ring-close to the cyclopropane 6. This tandem process is related to the previously described reactions that bear aldehydes or imines in place of Michael

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 β-amino ketones (15 examples) and the cyclopropanation of allylic amines (4 examples). Hydrogenation of an epoxyannulation product proceeded with good diastereoselectivity.

Heavily Substituted Atropisomeric Diarylamines by Unactivated Smiles Rearrangement of N-Aryl Anthranilamides

Diarylamines find use as metal ligands and as structural components of drug molecules, and are commonly made by metal-catalyzed C-N coupling. However, the limited tolerance to steric hindrance of these couplings restricts the synthetic availability of more substituted diarylamines. Here we report a remarkable variant of the Smiles rearrangement that employs readily accessible N-aryl anthranilamides as precursors to diarylamines. Conformational predisposition of the anthranilamide starting material brings the aryl rings into proximity and allows the rearrangement to take place despite the absence of electron-withdrawing substituents, and even with sterically encumbered doubly ortho-substituted substrates. Some of the diarylamine products are resolvable into atropisomeric enantiomers, and are the first simple diarylamines to display atropisomerism.

Enantioselective Synthesis of the Cyclopiazonic Acid Family Using Sulfur Ylides

Abstract A convergent, nine‐step (LLS), enantioselective synthesis of α‐cyclopiazonic acid and related natural products is reported. The route features a) an enantioselective aziridination of an imine with a chiral sulfur ylide; b) a bioinspired (3+2)‐cycloaddition of the aziridine onto an alkene; and c) installation of the acetyltetramic acid by an unprecedented tandem carbonylative lactamization/N−O cleavage of a bromoisoxazole.

Consecutive Ring Expansion and Contraction for the Synthesis of 1‐Aryl Tetrahydroisoquinolines and Tetrahydrobenzazepines from Readily Available Heterocyclic Precursors

Tetrahydroisoquinolines and tetrahydrobenzazepines were prepared by acid-promoted ring contraction of cyclic ureas, which were themselves formed by ring expansion of indolines and tetrahydroquinolines. The consequent overall one-carbon insertion reaction gives these 6- and 7-membered heterocyclic scaffolds in three steps from readily available precursors. Other ring sizes may be formed by an alternative elimination reaction of bicyclic structures. Scalability of the method was demonstrated by operating it in a flow system.