Synthetic probes for the study of biological function

From its beginnings, organic chemistry has been a partner to biology, often crossing the artificial boundary between the sciences to the benefit of both disciplines. This is even reflected in the use of the adjective “organic” to refer to the chemistry of carbon. As the field has matured, it has continued to address matters of structure and synthesis to increasingly encompass the grand challenge of designing and preparing molecules having a particular function. All three of these come together in the pursuit of new chemical probes for use in chemical biology

A combined intramolecular Diels-Alder/intramolecular Schmidt reaction: Formal synthesis of (±)-stenine

Four stereocenters and three rings are established in one step in a new formal synthesis of (±)-stenine (see scheme). This key reaction cascade consists of an intramolecular Diels-Alder reaction followed by an intramolecular Schmidt reaction. The resulting tricyclic intermediate was readily transformed into a known intermediate en route to stenine, thus completing the formal synthesis

Cation-π control of regiochemistry of intramolecular Schmidt reactions en route to bridged bicyclic lactams

The regiochemistry of the intramolecular Schmidt reaction of 2-substituted ketones has proved susceptible to control by the placement of an aromatic group at an adjacent position, permitting the selective formation of a series of bridged bicyclic lactams from these substrates. This phenomenon is ascribed to the presence of stabilizing through-space interactions between the positively charged leaving group and the aromatic substituents in a key azidohydrin intermediate

Aspects et évaluation post-thérapeutiques des lésions du foie après traitement non chirurgical

The main non-surgical treatments for liver lesions include chemotherapy, targeted treatments, chemoembolization and radiofrequency ablation. The post-treatment imaging features are variable and depend on the initial appearance of the lesion, the type of treatment and the imaging modality. Evaluation of tumour response to treatment is important. RECIST criteria based on unidimensional lesion measurements may not always be appropriate. Other evaluation criteria (Choi for GIST, EASL for HCC or Chun criteria.) may be more relevant

Synthesis, structural analysis, and reactivity of bridged orthoamides by intramolecular schmidt reaction

Intramolecular Schmidt reactions can be reliably steered toward bridged heterocycles containing orthoamides in high yields. The ketal tether enhances the control of regioselectivity in the migration of the bond distal to the reactive azide nucleophile, thus providing the first examples of the intramolecular Schmidt reaction proceeding with a complete regioselectivity en route to bridged products. The method is broad in scope and allows for systematic study of compounds that are analogous to elusive tetrahedral intermediates of amide addition reactions. Some initial reactivity and structural profiling of these compounds are also reported

Efficient access to sp3-rich tricyclic amine scaffolds through Diels-Alder reactions of azide-containing silyloxydienes

The preparation of sp3-rich scaffolds to obtain more natural product-like libraries for incorporation into screening decks is challenging. Here, we describe the use of a Diels-Alder reaction between an enone and an azide-containing silyloxydiene to gain efficient access to complex tricyclic amine scaffolds. Derivatization of these scaffolds provided a library of 80 amines, amides, sulfonamides, quinolines and indolenines, all in >20 mg quantities and >90% purities. These library compounds displayed properties more similar to alkaloid natural products than to drugs and commercial drug-like libraries, as shown by a high proportion of sp3 carbon centers

Aryl nitrenium ions from N-alkyl-N-arylamino-diazonium precursors: Synthesis and reactivity

A means of generating an N-alkyl-N-arylaminodiazonium ion, which then loses nitrogen to form a reactive aryl nitrenium intermediate, is described. In this sequence, a set of triazenyl acetonitriles was synthesized by nucleophilic addition of a nitrile anion to an aryl azide followed by temperature-dependent alkylation at either of two nucleophilic triazenyl nitrogen atoms. An α,α-disubstituted acetonitrile and N-arylaminodiazonium moiety (or aryl nitrenium ion upon loss of N2) are embedded in the resulting 1,3,3-trisubsituted triazene, which undergoes liberation and recombination of these two components under acidic conditions to yield an α-arylated acetonitrile containing an all-carbon-quaternary center. We propose that the N-alkyl-N-arylaminodiazonium ion loses nitrogen to generate an aryl nitrenium species, which then reacts with an α,α-disubstituted acetonitrile either at the para- or meta-position of the aromatic ring to afford p-alkylaminoaryl acetonitrile derivatives or 3,3-substituted 1-methylindolin-2-imines, depending on the substrates and conditions

Corey-Chaykovsky epoxidation of twisted amides: Synthesis and reactivity of bridged spiro-epoxyamines

The first example of a Corey-Chaykovsky epoxidation employing amides as substrates is described. Medium-bridged twisted amides serve as precursors to a family of isolable aminoepoxides. The reactivity of bridged spiro-epoxyamines is also investigated

Reagent-controlled regiodivergent ring expansions of steroids

Ring expansion provides a powerful way of introducing a heteroatom substituent into a carbocyclic framework. However, such reactions are often limited by the tendency of a given substrate to afford only one of the two rearrangement products or fail to achieve high selectivity at all. These limitations are particularly acute when seeking to carry out late-stage functionalization of natural products as starting points in drug discovery. In this work, we present a stereoelectronically controlled ring expansion sequence towards selective and flexible access to complementary ring systems derived from common steroidal substrates. Chemical diversification of the reaction intermediate affords over 100 isomerically pure analogs with spatial and functional diversity. This regiodivergent rearrangement, and the concept of using chiral reagents to affect regiocontrol in chiral natural products, should be broadly applicable to late-stage natural product diversification programs

Synthesis of cyclic 1,3-diols as scaffolds for spatially directed libraries

A useful design element in small molecule libraries is spatial diversity, in which binding moieties are systematically directed toward different regions of three-dimensional space. One way of achieving this is through the use of conformationally diverse scaffolds onto which various binding moieties can be placed. Such scaffolds can represent synthetic challenges of their own. In this paper, we describe a new route to chiral, cyclic 1,3-diol building blocks that features silylated dithianes as relay linchpins. These diols are subsequently used for the construction of a 24-compound pilot library bearing two amino acid residues