The Diels-Alder reaction is a cornerstone in organic synthesis, forming two carbon-carbon bonds and up to four new stereogenic centers in one step. No naturally occurring enzymes have been shown to catalyze bimolecular Diels-Alder reactions. We describe the de novo computational design and experimental characterization of enzymes catalyzing a bimolecular Diels-Alder reaction with high stereoselectivity and substrate specificity. X-ray crystallography confirms that the structure matches the design for the most active of the enzymes, and binding site substitutions reprogram the substrate specificity. Designed stereoselective catalysts for carbon-carbon bond-forming reactions should be broadly useful in synthetic chemistry.

Dicationic (bpy)Pt(II) complexes were found to catalyze the intramolecular hydrohydrazination of alkenes. Reaction optimization revealed Pt(bpy)Cl(2)(10 mol %) and AgOTf (20 mol %) in DMF-d(7) to be an effective catalyst system for the conversion of substituted hydrazides to five- and six-membered N-amino lactams (N-amino = N-acetamido at 120 degrees C, N-phthalimido at 80 degrees C,(-)OTf = trifluoromethanesulfonate). Of the four possible regioisomeric products, only the product of 5-exo cyclization at the proximal nitrogen is formed, without reaction at the distal nitrogen or 6-endo cyclization. The resting states were found to be a 2:1 Pt-amidate complex (25, for N-acetamido) of the deprotonated hydrazide and a Pt-alkyl complex of the cyclized pyrrolidinone (20 for N-phthalimido). Both complexes are catalytically competent. Catalysis using 25 as the precatalyst shows no rate dependence on added acid (HOTf) or base (2,6-lutidine). The available mechanistic data are all consistent with a mechanism involving N-H activation of the hydrazide, followed by insertion of the alkene into the Pt-N bond, and finally protonation of the resulting cyclized alkyl complex by hydrazide to release the hydrohydrazination product and regenerate the active Pt-amidate catalyst.

We report a highly regioselective metal-free oxidative cyclization of sulfonamides onto tethered, unactivated alkenes using hypervalent iodine and Brønsted acids. Under these conditions the acid counterion is incorporated into the cyclized products providing an overall aminotrifluoroacetoxylation of the alkene. An unusual preference for endo ring closure is exhibited in contrast to existing exo selective methods. Multiple ring sizes can be formed to access functionalized pyrrolidines, piperidines, and azepanes with a general preference for endo cyclization. A variety of substrate substitution patterns were tolerated to provide nitrogen-containing heterocycles with high regioselectivities and good to excellent diastereoselectivities.

The mechanism of the Pd-catalyzed diamination and carboamination of alkenes promoted by N-fluorobenzenesulfonimide (NFBS) was investigated. Stereochemical labeling experiments established that the diamination reaction proceeds via overall syn addition of the two nitrogen groups, whereas carboamination is the result of an anti addition of arene and nitrogen to the alkene. The intermediate Pd-alkyl complex arising from aminopalladation was observed, and an X-ray crystal structure of its 2,2'-bipyridine (bipy) complex was obtained, revealing strong chelation of the amide protecting group to palladium. Aminopalladation was shown to be an anti-selective process in both the presence and the absence of added ligands, proceeding via external attack of the nitrogen on a Pd-coordinated alkene. The intermediate Pd-alkyl complex was converted to diamination product upon exposure to NFBS with inversion of configuration via oxidative addition followed by dissociation of the benzenesulfonimide anion and S(N)2 displacement of the Pd-C bond. Conversely, arylation of the Pd-alkyl complex proceeds via retention of stereochemistry, consistent with C-H activation of the arene at the Pd(IV) center. A small intermolecular isotope effect (k(H)/k(D)= 1.1) and a large intramolecular isotope effect (k(H)/k(D)= 4) were measured for this process, indicating that C-H activation occurs via a poorly selective product-determining coordination of the arene followed by a highly selective C-H activation. Competition between arenes reveals an unusual reactivity order of toluene > benzene > bromobenzene > anisole.

This report describes a unique Pd-catalyzed oxidative carboamination of protected aminoalkenes in which inexpensive unactivated nucleophilic arenes are incorporated to give carboamination products in good yields. A variety of protected amide and carbamate groups are tolerated, and various five-, six-, and seven-membered rings are formed in good yields. Under these conditions, halobenzenes are activated at the C-H bond rather than the C-X bond, and very high regioselectivity for the para substitution product is observed in all cases. We propose that this carboamination takes place via electrophilic aromatic substitution of a Pd(IV) alkyl intermediate.

A remarkable Pd-catalyzed diamination of unactivated alkenes using N-fluorobenzenesulfonimide (NFBS) as an aminating reagent is described. The reaction occurs in an intra/intermolecular fashion, incorporating one nitrogen donor from the substrate and the other from the NFBS, thereby generating cyclic diamine derivatives in a single step. The products are differentially protected at both nitrogens, allowing for maximal synthetic flexibility. The intermediacy of the Pd(IV) species is proposed to be responsible for the unusual reactivity of NFBS.

A mild and facile Pd-catalyzed intramolecular hydroamination of unactivated alkenes is described. This reaction takes place at room temperature and is tolerant of synthetically useful acid-sensitive functional groups. The formation of hydroamination products rather than oxidative amination products is due to the use of a tridentate ligand on Pd which effectively inhibits beta-hydride elimination.

The reactions of the bis(cyclopentadienyl)(tert-butylimido)zirconium complex (Cp(2)Zr=N-t-Bu)(THF)(1) with epoxides, aziridines, and episulfides were investigated. Heterocycles without accessible beta-hydrogens undergo insertion/protonation of the C-X bond to produce 1,2-amino alcohols (X = O) and 1,2-diamines (X = NR), whereas heterocycles with accessible beta-hydrogens undergo elimination/protonation to produce allylic alcohols (X = O) and allylic sulfides (X = S). Mechanistic investigations support a stepwise pathway with zwitterionic intermediates for the first reaction class and a concerted pathway for the second reaction class. Additionally, the feasibility of chirality transfer from the planar-chiral ebthi (ebthi = ethylenebis(tetrahydroindenyl)) ligand was demonstrated with a chiral analogue,(ebthi)-Zr=NAr(THF)(Ar = 2,6-dimethylphenyl), 2, through the diastereoselective ring opening of meso epoxides.

The mechanisms of the rearrangements and stereoinversion of azametallacyclobutenes generated via [2+2] cycloaddition of allenes and imidozirconium complexes have been studied. Metallacycles derived from allenes bearing beta-hydrogen atoms racemize at room temperature by reversible beta-hydride elimination, a process which is also responsible for their eventual conversion to monoazadiene complexes. Metallacycles derived from diarylallenes racemize by reversible thermal bond homolysis at 95 degrees C; racemization of these metallacycles is also catalyzed by mild oxidants.