Discovery of enantioselective catalytic reactions for the preparation of chiral compounds from readily available precursors, using scalable and environmentally benign chemistry, can greatly impact their design, synthesis and eventually manufacture on scale. Functionalized cyclobutanes and cyclobutenes are important structural motifs seen in many bioactive natural products and pharmaceutically relevant small molecules. They are also useful precursors for other classes of organic compounds such as other cycloalkane derivatives, heterocyclic compounds, stereo-defined 1,3-dienes and ligands for catalytic asymmetric synthesis. The simplest approach to make cyclobutenes is through an enantioselective [2+2]-cycloaddition between an alkyne and an alkenyl derivative, a reaction which has a long history. Yet known reactions of this class that give acceptable enantioselectivities are of very narrow scope and are strictly limited to activated alkynes and highly reactive alkenes. Here we disclose a broadly applicable enantioselective [2+2]cycloaddition between wide variety of alkynes and alkenyl derivatives, two of the most abundant classes of organic precursors. The key cycloaddition reaction employs catalysts derived from readily synthesized ligands and an earthabundant metal, cobalt. Over 50 different cyclobutenes with enantioselectivities in the range of 86-97% ee are documented. With the diverse functional groups present in these compounds, further diastereoselective transformations are easily envisaged for synthesis of highly functionalized cyclobutanes and cyclobutenes. Some of the novel observations made during these studies including a key role of a cationic Co(I)-intermediate, ligand and counter ion effects on the reactions, can be expected to have broad implications in homogeneous catalysis beyond the highly valuable synthetic intermediates that are accessible by this route.

Much of the recent work on catalytic hydroboration of alkenes has focused on simple alkenes and styrene derivatives with few examples of reactions of 1,3-dienes, which have been reported to undergo mostly 1,4-additions to give allylic boronates. We find that reduced cobalt catalysts generated from 1,n-bis-diphenylphosphinoalkane complexes [Ph 2 P-(CH 2) n-PPh 2 ]CoX 2 ; n = 1~5) or from (2-oxazolinyl)phenyldiarylphosphine complexes [(G-PHOX)CoX 2 ] effect selective 1,2-, 1,4-, or 4,3-additions of pinacolborane (HBPin) to a variety of 1,3-dienes depending on the ligands chosen. Conditions have been found to optimize the 1,2-additions. The reactive catalysts can be generated from the cobalt (II)-complexes using trimethylaluminum, methyl aluminoxane or activated zinc in the presence of sodium tetrakis[(3,5-trifluoromethyl)phenyl]borate (NaBARF). The complex, (dppp)CoCl 2 , gives the best results (ratio of 1,2-to 1,4-addition >95:5) for a variety of linear terminal 1,3-dienes and 2-substituted 1,3-dienes. The [(PHOX)CoX 2 ] (X = Cl, Br) complexes give mostly 1,4-addition with linear unsubstituted 1,3-dienes, but, surprisingly selective 1,2-additions with 2-substituted or 2,3-disubstituted 1,3-dienes. Isolated and fully characterized (X-ray crystallography) Co(I)-complexes, (dppp) 3 Co 2 Cl 2 and [(S,S)-BDPP] 3 Co 2 Cl 2 , do not catalyze the reaction unless activated by a Lewis acid or NaBARF, suggesting a key role for a cationic Co(I) species in the catalytic cycle. Regio-and enantioselective 1,2-hydroborations of 2substituted 1,3-dienes are best accomplished using a catalyst prepared via activation of a chiral phosphinooxazoline-cobalt(II) complex with zinc and NaBARF. A number of common functional groups, among them,-OBn,-OTBS,-OTs, N-phthalimidogroups, are tolerated and er's >95:5

Stereoselective self-sorting of koneramines and thiokoneramines, which are N3 ligands, evolved from the system of pyridine-2-carboxaldehyde, mono-N-substituted ethylenediamine, primary alcohol or thiol, is observed when metal ions such as Ni(ii), Cu(ii), Zn(ii) and Cd(ii) are added as external stimuli to isolate the emergent molecule.

Conspectus One of the major challenges facing organic synthesis in the 21st century is the utilization of abundantly available feedstock chemicals for fine chemical synthesis. Regio- and enantioselective union of easily accessible 1,3-dienes and other feedstocks like ethylene, alkyl acrylates, and aldehydes can provide valuable building blocks adorned with latent functionalities for further synthetic elaboration. Through an approach that relies on mechanistic insights and systematic examination of ligand and counterion effects, we developed an efficient cobalt-based catalytic system [(P∼P)­CoX2/Me3Al] (P∼P = bisphosphine) to effect the first enantioselective heterodimerization of several types of 1,3-dienes with ethylene. In addition to simple cyclic and acyclic dienes, siloxy-1,3-dienes participate in this reaction, giving highly functionalized, nearly enantiopure silyl enolates, which can be used for subsequent C–C and C–X bond-forming reactions. As our understanding of the mechanism of this reaction improved, our attention was drawn to more challenging partners like alkyl acrylates (one of the largest volume feedstocks) as the olefin partners instead of ethylene. Prompted by the intrinsic limitations of using aluminum alkyls as the activators for this reaction, we explored the fundamental chemistry of the lesser known (P∼P)­Co(I)X species and discovered that in the presence of halide sequestering agents, such as sodium tetrakis­[3,5-bis­(trifluoromethyl)­phenyl]­borate (NaBARF) or (C6F5)3B, certain chiral bisphosphine complexes are superb catalysts for regio- and enantioselective heterodimerization of 1,3-dienes and alkyl acrylates. We have since found that these cationic Co­(I) catalysts, most conveniently prepared in situ by reduction of the corresponding cobalt­(II) halide complexes by zinc in the presence of NaBARF, promote enantioselective [2 + 2]-cycloaddition between alkynes and an astonishing variety of alkenyl derivatives to give highly functionalized cyclobutenes. In reactions between 1,3-enynes and ethylene, the [2 + 2]-cycloaddition between the alkyne and ethylene is followed by a 1,4-addition of ethylene in a tandem fashion to give nearly enantiopure cyclobutanes with an all-carbon quaternary center, giving a set of molecules that maps well into many medicinally relevant compounds. In another application, we find that the cationic Co­(I)-catalysts promote highly selective hydroacylation and 1,2-hydroboration of prochiral 1,3-dienes. Further, we find that a cationic Co­(I)-catalyst promotes cycloisomerization followed by hydroalkenylation of 1,6-enynes to produce highly functionalized carbo- and heterocyclic compounds. Surprisingly the regioselectivity of the alkene addition depends on whether it is a simple alkene or an acrylate, and the acrylate addition produces an uncommon Z-adduct. This Account will provide a summary of the enabling basic discoveries and the attendant developments that led to the unique cationic Co­(I)-complexes as catalysts for disparate C–C and C–B bond-forming reactions. It...

Ketones are among the most widely used intermediates in organic synthesis, and their synthesis from inexpensive feedstocks could be quite impactful. Regio-and enantioselective hydroacylation reactions of dienes provide facile entry into useful ketone-bearing chiral motifs with an additional latent functionality (alkene) suitable for further elaboration. Three classes of dienes, 2-or 4-monosubstituted and 2,4-disubstituted 1,3-dienes, undergo cobalt(I)-catalyzed regio-and enantioselective hydroacylation, giving products with high enantiomeric ratios (er). These reactions are highly dependent on the ligands, and we have identified the most useful ligands and reaction conditions for each class of dienes. 2-Substituted and 2,4-disubstituted dienes predominantly undergo 1,2-addition, whereas 4-substituted terminal dienes give highly enantioselective 4,1-or 4,3-hydroacylation depending on the aldehyde, aliphatic aldehydes giving 4,1-addition and aromatic aldehydes giving 4,3-addition. Included among the substrates are feedstock dienes, isoprene (US$1.4/kg) and myrcene (US$129/kg), and several common aldehydes. We propose an oxidative dimerization mechanism that involves a Co(I)/Co(III) redox cycle that appears to be initiated by a cationic Co(I) intermediate. Studies of reactions using isolated neutral and cationic Co(I) complexes confirm the critical role of the cationic intermediates in these reactions. Enantioselective 1,2-hydroacylation of 2-trimethylsiloxy-1,3-diene reveals a hitherto undisclosed route to chiral siloxy-protected aldols. Finally, facile syntheses of the anti-inflammatory drug (S)-Flobufen (2 steps, 92% yield, >99:1 er) and the food additive (S)-Dihydrotagetone (1 step, 83% yield; 96:4 er) from isoprene illustrate the power of this method for the preparation of commercially relevant compounds.