A compound’s overall contour impacts its ability to elicit biological response, rendering access to distinctly shaped molecules desirable. A natural product’s framework can be modified, but only if it is abundant and contains suitably modifiable functional groups. Here we introduce a programmable strategy for concise synthesis of precisely altered scaffolds of scarce bridged polycyclic alkaloids. Central to our approach is a scalable catalytic multi-component process that delivers diastereo- and enantiomerically enriched tertiary homoallylic alcohols bearing differentiable alkenyl moieties. We used one product to launch progressively divergent syntheses of a naturally occurring alkaloid and its precisely expanded, contracted and/or distorted framework analogues (average number of steps/scaffold of seven). In vitro testing showed that a skeleton expanded by one methylene in two regions is cytotoxic against four types of cancer cell line. Mechanistic and computational studies offer an account for several unanticipated selectivity trends.

Racemic vinylallenes are shown to be effective substrates for catalytic multicomponent diastereo- and enantioselective 1,6-conjugate addition of multifunctional allyl moieties to easily accessible α,β,γ,δ-unsaturated diesters. Reactions may be catalyzed by 5.0 mol % of a readily accessible NHC-Cu complex at ambient temperature, and other than a vinylallene, involve B2 (pin)2 and an α,β,γ,δ-unsaturated diester. A variety of vinylallenes were converted to products bearing a Z-trisubstituted alkenyl-B(pin) moiety, a vinyl group, a β,γ-unsaturated diester unit, and vicinal stereogenic centers in up to 67 % yield, 87:13 Z/E ratio, >98:2 d.r., and 98:2 e.r. Chemoselective modifications involving the alkenyl-B(pin), the vinyl, or the 1,2-disubstituted olefin moieties were carried out to demonstrate versatility and utility. Stereochemical models, based on mechanistic and DFT studies, demonstrate the dynamic behavior of intermediated Cu-allyl species and account for various selectivity profiles.

Catalytic enantioselective boron-hydride additions to 1,3-enynes, which afford allenyl-B(pin) (pin = pinacolato) products, are disclosed. Transformations are promoted by a readily accessible bis-phosphine-Cu complex and involve commercially available HB(pin). The method is applicable to aryl- and alkyl-substituted 1,3-enynes. Trisubstituted allenyl-B(pin) products were generated in 52-80% yield and, in most cases, in >98:2 allenyl:propargyl and 92:8-99:1 enantiomeric ratio. Utility is highlighted through a highly diastereoselective addition to an aldehyde, and a stereospecific catalytic cross-coupling process that delivers an enantiomerically enriched allene with three carbon-based substituents. The following key mechanistic attributes are elucidated: (1) Spectroscopic and computational investigations indicate that low enantioselectivity can arise from loss of kinetic stereoselectivity, which, as suggested by experimental evidence, may occur by formation of a propargylic anion generated by heterolytic Cu-C cleavage. This is particularly a problem when trapping of the Cu-allenyl intermediate is slow, namely, when an electron deficient 1,3-enyne or a less reactive boron-hydride reagent (e.g., HB(dan) (dan = naphthalene-1,8-diaminato)) is used or under non optimal conditions (e.g., lower boron-hydride concentration causing slower trapping). (2) With enynes that contain a sterically demanding o-aryl substituent considerable amounts of the propargyl-B(pin) isomer may be generated (25-96%) because a less sterically demanding transition state for Cu/B exchange becomes favorable. (3) The phosphine ligand can promote isomerization of the enantiomerically enriched allenyl-B(pin) product; accordingly, lower ligand loading might at times be optimal. (4) Catalytic cross-coupling with an enantiomerically enriched allenyl-B(pin) compound might proceed with high stereospecificity (e.g., phosphine-Pd-catalyzed cross-coupling) or lead to considerable racemization (e.g., phosphine-Cu-catalyzed allylic substitution).

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

A variety of chiral 2‐oxindoles is prepared by the title amination of oxindoles with azodicarboxylates in high yields and excellent enantioselectivities.

A highly enantioselective α-amination of 3-substituted oxindoles with azodicarboxylates catalyzed by amino acids-derived chiral phosphine catalysts is reported. The corresponding products containing a tetrasubstituted carbon center attached to a nitrogen atom at the C-3 position of the oxindole were obtained in high yields and with up to 98% ee.

The total synthesis of gelsedilam, which features a highly diastereoselective thiol conjugate addition-intramolecular aldol reaction to install the strained and caged [3.2.2] bridged ring system and highly efficient NiCl2 /NaBH4 -mediated four-step transformation in one-pot to construct its five-membered lactam ring is reported. The synthesis requires only 18 linear steps from the known compounds, providing useful strategies for the construction of the intricate ring system in the synthesis of related gelsedine-type alkaloids.

Enantioselective Robinson-type annulation reaction between β-ketoamide and α,β-unsaturated ketone was developed by utilizing the amino acid derived primary-secondary diamine catalysts. The less reactive acyclic β-ketoamides employed as both electrophile and nucleophile are reported in this asymmetric tandem reaction. A number of chiral cyclohexenone derivatives containing an amide group were obtained in high yields and good selectivities.

A Pd-catalyzed enantiospecific formal [3 + 2] cycloaddition between chiral aziridines and indoles has been developed. With this method, chiral pyrroloindolines in enantiomerically pure forms were constructed in high yields and diastereoselectivities under mild conditions.

An efficient method for the construction of chiral spirooxindole-chroman and spirooxindole-tetrahydrothiophene scaffolds with three consecutive chiral centers including an all-carbon quaternary spirocenter has been developed. This method features an asymmetric thia/oxa-Michael-Michael cascade sequence in a single operation in the presence of chiral tertiary amine-thioureas as the catalysts, providing the desired products in good chemical yields and optical purities.

An efficient organocatalytic aza-Michael-Michael cascade reaction for the asymmetric synthesis of highly functionalized spirooxindole tetrahydroquinolines has been reported through a formal [4+2] annulation strategy.