Cinchona‐based Primary Amine Catalysis in the Asymmetric Functionalization of Carbonyl Compounds

Asymmetric aminocatalysis exploits the potential of chiral primary and secondary amines to catalyze asymmetric reactions. It has greatly simplified the functionalization of carbonyl compounds while ensuring high enantioselectivity. Recent advances in cinchona‐based primary amine catalysis have provided new synthetic opportunities and conceptual perspectives for successfully attacking major challenges in carbonyl compound chemistry, which traditional approaches have not been able to address. This Review outlines the historical context for the development of this catalyst class while charting the landmark discoveries and applications that have further expanded the synthetic potential of aminocatalysis.     

Pyrrole aminoimidazole alkaloid metabiosynthesis with marine sponges Agelas conifera and Stylissa caribica

Game-SET-match: Pyrrole aminoimidazole alkaloids (PAIs) are metabiosynthesized from chlorinated analogues of oroidin by cell-free enzyme preparations from PAI-producing sponges. Evidence and implications for the biosynthesis of PAIs include putative single-electron transfers (SETs) that promote C-C bond-forming reactions of precursors.     

Netamines A-G: seven new tricyclic guanidine alkaloids from the marine sponge Biemna laboutei

In our continuing program to identify bioactive compounds from marine invertebrates, the MeOH/EtOAc (1:1) extract of three collections of the Madagascar sponge, Biemna laboutei, was found to be cytotoxic to a series of human tumor cells. From the two sponges, seven new guanidine alkaloids, designated netamines A-G (1-7), have been isolated and their structures elucidated. Compounds 3 and 4 were found to be cytotoxic against three tumor cells with GI₅₀ values in the micromolar range.     

Controlling the regiochemistry of radical cyclizations

This review describes the results of our recent studies on the control of the regiochemistry of radical cyclizations. N-vinylic alpha-chloroacetamides generally cyclized in a 5-endo-trig manner to give five-membered lactams, whereas 4-exo-trig cyclization occurred when the cyclized radical intermediates were highly stabilized by an adjacent phenyl or phenylthio group to afford beta-lactams. The 5-exo or 6-exo cyclization of aryl radicals onto the alkenic bond of enamides could be shifted to the corresponding 6-endo or 7-endo mode of cyclization by a positional change of the carbonyl group of enamides. The 6-endo- and 7-endo-selective aryl radical cyclizations were applied to radical cascades for the synthesis of alkaloids such as phenanthroindolizidine, cephalotaxine skeleton, and lennoxamine. The 5-exo-trig cyclization of an alkyl radical onto the alkenyl bond of enamides could also be shifted to the 6-endo mode by a positional change of the carbonyl group of enamides. The 6-endo- selective cyclization was applied to the radical cascade to afford a cylindricine skeleton. Other examples of controlling the regiochemistry of radical cyclizations and their applications to the synthesis of natural products are also discussed.     

5,6-Dihydropyrrolo[2,1-b]isoquinolines as scaffolds for synthesis of lamellarin analogues

Efficient modular synthetic routes to open chain marine alkaloids such as lamellarins have been developed. 5,6-Dihydropyrrolo[2,1-b]isoquinoline scaffolds were prepared, and protocols enabling regioselective bromination followed by Suzuki cross-coupling were established for the introduction of aryl groups onto the 2- and 3-positions.     

Planned and unplanned halogenations in route to selected oroidin alkaloids

Highly diastereoselective, substrate-controlled, halogenation/ring contraction sequences delivered the naturally occurring chlorinated and unnatural brominated and iodinated axinellamine core structure. An unexpected azide displacement of the chlorinated cyclopentane, which proceeded with retention of stereochemistry, suggested a modification of the Scheuer/Kinnel proposal that may account for the related natural product massadine. Two unsuccessful routes to access the stereochemistry proposed for palau'amine were S_N2 displacement of the bromo- and iodocyclopentane with excess chloride anion and an intramolecular directed chlorination pathway. Finally, an unexpected chlorination during our phakellstatin synthesis proceeded with retention of stereochemistry during tosylation possibly resulting from neighboring group participation.