A convenient and versatile SNAr-decarboxylation protocol for the construction of C(sp2)-C(sp3) bonds.

Increasing saturation (Fsp3) remains a central strategy in the optimization of properties of molecules during drug discovery. Here, we describe a versatile and operationally simple one-pot procedure for accomplishing this goal via a nucleophilic aromatic substitution-decarboxylation sequence to construct C(sp2)-C(sp3) bonds. The method is tolerant of a variety of biologically privileged moieties and has been demonstrated in a library format.

Development of a Late-Stage Diversification Strategy for the 4- and 5-Positions of 4,5,6-Trisubstituted Indazoles.

Indazoles represent a privileged motif in drug discovery. However, the formation of highly substituted indazoles can require the execution of lengthy synthetic routes with minimal opportunities to introduce diversity. In this report, we disclose the development of a late-stage diversification strategy for the 4- and 5-positions of 4,5,6-trisubstituted indazoles. A regioselective C-H functionalization and subsequent nucleophilic aromatic substitution provide two sequential points of diversification. The synthetic sequence delivers rapid access to an array of 4,5,6-trisubstituted indazoles in only four steps from readily available starting materials.

Using the Competing Enantioselective Conversion Method to Assign the Absolute Configuration of Cyclic Amines with Bode's Acylation Reagents.

The competing enantioselective conversion (CEC) method is a quick and reliable means to determine absolute configuration. Previously, Bode's chiral acylated hydroxamic acids were used to determine the stereochemistry of primary amines, as well as cyclic and acyclic secondary amines. The enantioselective acylation has been evaluated for 4-, 5-, and 6-membered cyclic secondary amines, including medicinally relevant compounds. The limitations of the method were studied through computational analysis and experimental results. Piperidines with substituents at the 2-position did not behave well unless the axial conformer was energetically accessible, which is consistent with the transition state geometries proposed by Bode and Kozlowski. Control experiments were performed to investigate the cause of degrading selectivity under the CEC reaction conditions. The present study expands the scope of the CEC method for secondary amines and provides a better understanding of the reaction profile.

Multifaceted Substrate-Ligand Interactions Promote the Copper-Catalyzed Hydroboration of Benzylidenecyclobutanes and Related Compounds.

A unified synthetic strategy to access tertiary four-membered carbo/heterocyclic boronic esters is reported. Use of a Cu(I) catalyst in combination with a modified dppbz ligand enables regioselective hydroboration of various trisubstituted benzylidenecyclobutanes and carbo/heterocyclic analogs. The reaction conditions are mild, and the method tolerates a wide range of medicinally relevant heteroarenes. The protocol can be conveniently conducted on gram-scale, and the tertiary boronic ester products undergo facile diversification into valuable targets. Reaction kinetics and computational studies indicate that the migratory insertion step is turnover-limiting and accelerated by electron-withdrawing groups on the dppbz ligand. Energy decomposition analysis (EDA) calculations reveal that electron-deficient P-aryl groups on the dppbz ligand enhance the T-shaped π/π interactions with the substrate and stabilize the migratory insertion transition state.

Total Synthesis of (-)-Himeradine†A.

(-)-Himeradine A is a complex lycopodium alkaloid with seven rings and ten stereogenic centers that shows anticancer activity against lymphoma L1210 cells. A total synthesis has been developed that builds off prior work on (+)-fastigiatine. A 2,4,6-trisubstitited piperidine ring forms the core of the quinolizidine segment, and was prepared by diastereoselective reduction of a pyridine and classic resolution of an intermediate. The remaining secondary amine was introduced with a catalyst-controlled Overman rearrangement. The piperidine segment was coupled in a B-alkyl Suzuki reaction with a bicyclic bromoenone, which was a key intermediate for the synthesis of (+)-fastigiatine. The final transformation featured a transannular Mannich reaction and cyclization to complete the quinolizidine. Five bonds and four new rings were generated in this one-pot procedure. (-)-Himeradine A was prepared in 17 steps in the longest linear sequence.

Biosynthesis-Inspired Approach to Kujounin A2 Using a Stereoselective Tsuji-Trost Alkylation.

A new biosynthesis was proposed for the kujounins A1 and A2 beginning from ascorbic acid, which in turn inspired a synthetic approach to kujounin A2. The ring system was assembled in two steps using a stereoselective Tsuji-Trost reaction followed by ozonolysis. The chemically labile disulfide was introduced in several more steps. These results will make kujounin and its analogues available for further evaluation.

Second-Generation Synthesis of (+)-Fastigiatine Inspired by Conformational Studies.

(+)-Fastigiatine is a complex alkaloid isolated from the alpine club moss Lycopodium fastigatum, most commonly found in New Zealand. It has been the subject of two successful synthetic campaigns. A second-generation route toward fastigiatine was developed to resolve two problematic steps from our initial synthesis. Selective reduction and protection of the C13 ketone improved the yield and reliability of the dibromocarbene ring expansion step. In the prior synthesis, cuprate addition to the C10 enone generated a 1:1 mixture of isomers in an advanced intermediate. Protection of the C13 alcohol with a large silyl group changed the conformational preference of the enone and led to a more selective conjugate addition to produce the desired ß-epimer at C10. MacMillan's decarboxylative photoredox addition method proved to be more practical than the prior aminomethyl cuprate addition chemistry. The second-generation synthesis is longer than the original but improves the selectivity and reproducibility of the overall route.

Determination of the Absolute Configuration of Cyclic Amines with Bode's Chiral Hydroxamic Esters Using the Competing Enantioselective Conversion Method.

The competing enantioselective conversion (CEC) strategy has been extended to cyclic amines. The basis for the CEC approach is the use of two complementary, enantioselective reactions to determine the configuration of the enantiopure substrate. Bode's chiral acylated hydroxamic acids are very effective enantioselective acylating agents for a variety of amines. Pseudoenantiomers of these acyl-transfer reagents were prepared and demonstrated to react with enantiopure cyclic amines with modest to high selectivity. The products were analyzed by ESI-MS to determine selectivity, and the results were used to assign the configuration of the amine substrate. The method was applicable to a variety of cyclic amines as well as primary amines and acyclic secondary amines. The method is limited to amines that are unhindered enough to react with the reagents, and not all amine substitution patters lead to high selectivity.