Sven P. Fritz

Stereoselective Organocatalytic Synthesis of Oxindoles with Adjacent Tetrasubstituted Stereocenters

Oxindoles with adjacent tetrasubstituted stereocenters were obtained in high yields and stereoselectivities by organocatalyzed conjugate addition reactions of monothiomalonates (MTMs) to isatin-derived N-Cbz ketimines. The method requires only a low catalyst loading (2 mol %) and proceeds under mild reaction conditions. Both enantiomers are accessible in good yields and excellent stereoselectivities by using either Takemotos catalyst or a cinchona alkaloid derivative. The synthetic methodology allowed establishment of a straightforward route to derivatives of the gastrin/cholecystokinin-B receptor antagonist AG-041R.

Organocatalytic Route to Dihydrocoumarins and Dihydroquinolinones in All Stereochemical Configurations

A straightforward stereodivergent route to dihydrocoumarins and dihydroquinolinones based on cinchona alkaloid catalyzed addition reactions of monothiomalonates (MTMs) to functionalized nitroolefins followed by deprotection and chemoselective cyclization has been developed. The synthesis proceeds under mild conditions and yields heterocycles with adjacent quaternary and tertiary stereogenic centers in very high yields and stereoselectivities. Moreover, full control over the relative and absolute configuration is achieved by the use of (pseudo)enantiomeric catalysts and the difference in reactivity of thioester versus oxoester moieties.

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.

Stereoselective Metal‐Free Synthesis of β‐Amino Thioesters with Tertiary and Quaternary Stereogenic Centers

β-Amino thioesters are important natural building blocks for the synthesis of numerous bioactive molecules. An organocatalyzed Mannich reaction was developed which provides direct and highly stereoselective access to acyclic β(2)- and β(2,3,3)-amino thioesters with adjacent tertiary and quaternary stereocenters. Mechanistic studies showed that the stereochemical course of the reaction can be controlled by the choice of the substrates. The β-amino thioesters were further functionalized by, for example, stereoselective decarboxylation to access β(2,3)-frameworks. In addition, the value of the β-amino thioesters was shown in coupling-reagent-free peptide synthesis.

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).

Organocatalytic stereoselective synthesis of acyclic γ-nitrothioesters with all-carbon quaternary stereogenic centers.

A method for the stereoselective synthesis of acyclic thioesters bearing adjacent quaternary and tertiary stereogenic centers under mild organocatalytic conditions was developed. α-Substituted monothiomalonates (MTMs) were used as thioester enolate equivalents. They reacted cleanly with nitroolefins in the presence of 1-6 mol % of cinchona alkaloid urea derivatives, and provided access to γ-nitrothioesters with quaternary stereocenters in high yields and diastereo- and enantioselectivities. Mechanistic investigations provided insight into the parameters that determine the stereoselectivity and showed that the diastereoselectivity can be controlled by the nature of the MTM substrate. The different reactivities of the three functional groups (oxoester, thioester, nitro moieties) within the conjugate addition products allowed for straightforward access to other compounds with quaternary stereogenic centers, such as γ-nitroaldehydes and γ-butyrolactams.

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.