A method is described which provides for the direct asymmetric catalytic synthesis of trisubstituted aziridines from imines and diazo compounds. While unactivated imines were not reactive to α-diazo ...carbonyl compounds in which the diazo carbon was disubstituted, N-Boc imines react with both α-diazo esters and α-diazo-N-acyloxazolidinones to give trisubstituted aziridines with excellent diastereo- and enantioselectivities.
A new catalyst is designed, synthesized, and evaluated for the asymmetric Michael addition of nitroalkanes to nitroalkenes. The obdurate nature of this reaction has made this a formidable challenge ...to subdue by asymmetric catalysis. The catalyst design includes a thiourea function to activate the nitroalkene by a double H-bond and a 4-dimethylaminopyridine unit to deprotonate the nitroalkane and to bind the resulting nitronate anion also by a double H-bond. The chiral scaffold for the catalyst is 2,2′-diamino-1,1′-binaphthalene (BINAM), and a bis-conjugate is prepared by the attachment of the thiourea unit and the dimethylaminopyridine moiety (DMAP) via the two amino groups. The resulting catalyst will effect the reaction of nitroalkanes to a variety of nitrostyrenes and gives excellent asymmetric inductions (91−95% ee) over a range of 10 substrates. Remarkably, the asymmetric induction increases with decreasing catalyst loading with the optimal compromise between rate and induction at a loading of 2 mol %.
A novel bis‐thiourea/2,2′‐diaminobinaphthalene (BINAM)‐based catalyst for the asymmetric aza‐Henry reaction has been developed. This catalyst promotes the reaction of N‐Boc imines with nitroalkanes ...to afford β‐nitroamines with good yields and high enantioselectivities. This catalyst has the advantage that it can be prepared in a single step from commercially available materials. A model is proposed for the catalyst action where both components of the reaction are activated simultaneously by hydrogen bonding. Regardless of the mechanism, the success of the present catalyst demonstrates the potential of bis‐thioureas as an interesting class of relatively unexplored catalysts.
The first chiral catalyst for the three‐component Ugi reaction was identified as a result of a screen of a large set of different BOROX catalysts. The BOROX catalysts were assembled in situ from a ...chiral biaryl ligand, an amine, water, BH3⋅SMe2 , and an alcohol or phenol. The catalyst screen included 13 different ligands, 12 amines, and 47 alcohols or phenols. The optimal catalyst system (LAP 8‐5‐47) provided α‐amino amides from an aldehyde, a secondary amine, and an isonitrile with excellent asymmetric induction. The catalytically active species is proposed to be an ion pair that consists of the chiral boroxinate anion and an iminium cation.
Harmonious arrangement of parts: A screen of BOROX catalysts that were generated in situ from 13 different ligands and 47 alcohols led to the identification of an effective combination for the catalytic asymmetric three‐component Ugi reaction. Experimental results suggest that the catalyst is a chiral polyborate anion, which then forms an ion pair with the iminium cation that is generated from aldehyde and secondary amine.
The development of a catalytic asymmetric method for the direct aminoallylation of aldehydes is described that gives high asymmetric inductions for a broad range of substrates including both aromatic ...and aliphatic aldehydes. This method allows for direct isolation of unprotected analytically pure homoallylic amines without chromatography. The unique catalyst system developed for this process involves the synergistic interaction between a chiral and a nonchiral Brønsted acid.
Chiral polyborate based Brønsted acids prepared from the VANOL and VAPOL ligands are known to catalyze the reaction of diarylmethyl imines with diazoesters to give cis-aziridines. In the present ...work, this same catalyst is shown to catalyze the reaction of the same imines with diazoacetamides to give trans-aziridines with the same high asymmetric inductions as seen with cis-aziridines, enabling the development of an unprecedented universal catalytic asymmetric aziridination protocol. The substrate scope is broad and includes imines prepared from both electron-rich and electron-poor aromatic aldehydes and also from 1°, 2°, and 3° aliphatic aldehydes. The face selectivity of the addition to the imine was found to be independent of the diazo compounds. The (S)-VANOL or (S)-VAPOL derived catalyst will cause both diazoesters and diazoacetamides to add to the Si-face of the imine when cis-aziridines are formed and both to add to the Re-face of the imine when trans-aziridines are formed.
The first enantioselective total syntheses of prenylflavonoid Diels–Alder natural products (−)‐kuwanon I, (+)‐kuwanon J, (−)‐brosimone A, and (−)‐brosimone B have been accomplished from a common ...intermediate based on a concise synthetic strategy. Key elements of the synthesis include a biosynthesis‐inspired asymmetric Diels–Alder cycloaddition mediated by a chiral ligand/boron Lewis acid, as well as a process involving regioselective Schenck ene reaction, reduction, and dehydration to realize a biomimetic dehydrogenation for generation of the required diene precursor. Furthermore, a remarkable tandem inter‐/intramolecular asymmetric Diels–Alder cycloaddition process was applied for the synthesis of (−)‐brosimone A.
Four in a row: The first enantioselective total syntheses of the prenylflavonoid natural products (−)‐kuwanon I, (+)‐kuwanon J, (−)‐brosimone A, and (−)‐brosimone B have been accomplished based on a concise synthetic strategy. Key elements of the synthesis include a biosynthesis‐inspired asymmetric Diels–Alder cycloaddition mediated by a chiral ligand/boron Lewis acid, as well as a process involving regioselective Schenck ene reaction, reduction, and dehydration.
VANOL and VAPOL ligands are known to react with three equivalents of B(OPh)3 to form a catalytic species that contains a boroxinate core with three boron atoms, and these have proven to be effective ...catalysts for a number of reactions. However, it was not known whether the closely related BINOL ligand will likewise form a boroxinate species. It had simply been observed that mixtures of BINOL and B(OPh)3 were very poor catalysts compared to the same mixtures with VANOL or VAPOL. Borate esters of BINOL have been investigated as chiral catalysts, and these include meso-borates, spiro-borates, and diborabicyclo-borate esters. Borate esters are often in equilibrium, and their structures can be determined by stoichiometry and/or thermodynamics, especially in the presence of a base. The present study examines the structures of borate esters of BINOL that are produced with different stoichiometric combinations of BINOL with B(OPh)3 in the presence and absence of a base. Depending on conditions, pyro-borates, spiro-borates, and boroxinate species can be generated and their effectiveness in a catalytic asymmetric aziridination was evaluated. The finding is that BINOL borate species are not necessarily inferior catalysts to those of VANOL and VAPOL but that, under the conditions, BINOL forms two different catalytic species (a boroxinate and a spiro-borate) that give opposite asymmetric inductions. However, many BINOL derivatives with substitutents in the 3- and 3′-positions gave only the boroxinate species and the 3,3′-Ph2BINOL ligand gave a boroxinate catalyst that gives excellent inductions in the aziridination reaction. BINOL derivatives with larger groups in the 3,3′-position will not form either spiro-borates or boroxinate species and thus are not effective catalysts at all.
The mechanism of the chiral VANOL-BOROX Brønsted acid catalyzed aziridination reaction of imines and ethyldiazoacetate has been studied using a combination of experimental kinetic isotope effects and ...theoretical calculations. A stepwise mechanism where reversible formation of a diazonium ion intermediate precedes rate-limiting ring closure to form the cis-aziridine is implicated. A revised model for the origin of enantio- and diastereoselectivity is proposed based on relative energies of the ring-closing transition structures.
The stereochemistry-determining step of the self-assembled chiral Brønsted acid-catalyzed aziridination reactions of MEDAM imines and three representative diazo nucleophiles has been studied using ...ONIOM(B3LYP/6-31G*:AM1) calculations. The origin of cis selectivity in the reactions of ethyldiazoacetate and trans selectivity in reactions of N-phenyldiazoacetamide can be understood on the basis of the difference in specific noncovalent interactions in the stereochemistry-determining transition state. A H-bonding interaction between the amidic hydrogen and an oxygen atom of the chiral counterion has been identified as the key interaction responsible for this reversal in diastereoselectivity. This hypothesis was validated when a 3° diazoamide lacking this interaction showed pronounced cis selectivity both experimentally and calculationally. Similar trends in diastereoselection were observed in analogous reactions catalyzed by triflic acid. The broad implications of these findings and their relevance to chiral Brønsted acid catalysis are discussed.
PDF
