(+)-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 β-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.

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.

A unified synthetic strategy to access tertiary four-membered carbo/heterocyclic boronic esters is reported. The use of a Cu­(I) catalyst in combination with a modified 1,2-bis­(diphenylphosphino)­benzene (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 a 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 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.

(−)‐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.

An undergraduate organic chemistry experiment has been developed that features asymmetric synthesis of an enantioenriched secondary alcohol, followed by determination of its absolute configuration using the competing enantioselective conversion (CEC) method. Students are given a ketone and an unknown enantiomer of CBS (Corey–Bakshi–Shibata) catalyst. This reaction forms an enantioenriched secondary alcohol of unknown absolute configuration. Students then determine the absolute configuration via the CEC method. The CEC method is a modern application of the Horeau method that runs parallel reactions using both enantiomers of a chiral acyl-transfer catalyst, homobenzotetramisole (HBTM). Reactions are quenched concurrently, and reaction rates are compared using thin-layer chromatography (TLC) and/or 1H nuclear magnetic resonance (NMR) spectroscopy to determine the fast and the slow reactions. By comparing the faster reaction to a previously determined mnemonic, the absolute configuration of the alcohol can be determined. From this information, students can then determine which enantiomer of CBS catalyst they used to form the enantioenriched alcohol. Both parts of this experiment were successfully completed in one 5 h lab section. This experiment provides an opportunity for discussion of important chemistry concepts including asymmetric synthesis, asymmetric catalysis, kinetic resolution, mechanism, transition state theory, and inert-atmosphere techniques.