Formal Synthesis of the Anti‐Angiogenic Polyketide (−)‐Borrelidin under Asymmetric Catalytic Control

Borrelidin ( 1 ) is a polyketide that possesses extremely potent anti‐angiogenesis activity. This paper describes its formal total synthesis by the most efficient route to date. This modular approach takes optimal benefit of asymmetric catalysis and permits the synthesis of analogues; in addition, the high yields and selectivities obtained eliminate the need for separation of stereoisomers. The upper half of borrelidin has been accessed by iterative copper‐catalysed asymmetric conjugate addition of methylmagnesium bromide, whereas synthesis of the lower half of the molecule was achieved by relying on asymmetric hydrogenation and cross‐methathesis as key steps.     

Asymmetric Synthesis of Chiral Sulfoximines through the S‐Alkylation of Sulfinamides

Innovation in drug discovery critically depends on the development of new bioisosteric groups. Chiral sulfoximines, which contain a tetrasubstituted sulfur atom that bears one nitrogen, one oxygen, and two different carbon substituents, represent an emerging chiral bioisostere in medicinal chemistry. Chiral sulfoximines are conventionally prepared by a stereospecific nitrene transfer reaction to chiral sulfoxides; however, the number of readily available chiral sulfoxides remains limited. Herein, we report the asymmetric synthesis of a class of hitherto difficult‐to‐access chiral sulfoximines with two structurally similar alkyl chains. Our synthetic approach is based on the sulfur‐selective alkylation of easily accessible chiral sulfinamides with commercially available reagents under simple and safe conditions. This stereospecific S‐alkylation offers a general and scalable approach to the asymmetric synthesis of chiral sulfoximines, which represent important substructures in bioactive molecules.     

Versatile In Situ Generated N‐Boc‐Imines: Application to Phase‐Transfer‐Catalyzed Asymmetric Mannich‐Type Reactions

The efficient construction of nitrogen‐containing organic compounds is a major challenge in chemical synthesis. Imines are one of the most important classes of electrophiles for this transformation. However, both the available imines and applicable nucleophiles for them are quite limited given the existing preparative methods. Described herein are imine precursors which generate reactive imines with a wide variety of substituents under mild basic conditions. This approach enables the construction of various nitrogen‐containing molecules which cannot be accessed by the traditional approach. The utility of the novel imine precursor was demonstrated in the asymmetric Mannich‐type reaction under phase‐transfer conditions.     

Asymmetric Synthesis of Less Accessible α‐Tertiary Amines from Alkynyl Z‐Ketimines

A highly stereoselective synthesis of hitherto less accessible chiral α‐tertiary amines with multiple structurally similar linear carbon chains was achieved through chiral auxiliary mediated addition of organolithium reagents to the geometrically well‐controlled alkynyl Z ‐ketimines. This stereoselective nucleophilic addition offers a general approach to the asymmetric synthesis of nitrogen‐containing chiral materials.     

Synthesis of α‐Chiral Butyrolactones by Highly Stereoselective Radical Transfer or Sequential Asymmetric Alkylations: Concise Preparation of Leupyrrin Moieties

Inspired by the bioactive natural metabolites leupyrrin A₁ and B₁, two novel stereoselective methods for the highly concise synthesis of densely substituted α‐chiral butyrolactones are reported. The first approach relies on an innovative three‐step Ti^III‐catalyzed radical reaction that proceeds with excellent chemo‐, regio‐, and stereoselectivity. The alternative route utilizes sequential asymmetric alkylations and enables asymmetric synthesis of the authentic α‐tetrasubstituted butyrolactone motif of the leupyrrins in only four steps from commercially available substrates.     

Asymmetric Synthesis of α,α‐Disubstituted Allylic Amines through Palladium‐Catalyzed Allylic Substitution

The first asymmetric synthesis of important α,α‐disubstituted N‐alkyl allyl amine scaffolds through allylic substitution is reported. This approach is based on palladium catalysis and features ample scope with respect to both the allylic precursor and amine reagent, and high asymmetric induction with enantiomeric ratios (e.r.) up to 98.5:1.5. The use of less‐reactive anilines is also feasible, providing enantioenriched α,α‐disubstituted N‐aryl allylic amines.     

A Divergent Synthetic Route to the Vallesamidine and Schizozygine Alkaloids: Total Synthesis of (+)‐Vallesamidine and (+)‐14,15‐Dehydrostrempeliopine

The total synthesis of representative members of the schizozygine alkaloids, (+)‐vallesamidine and (+)‐14,15‐dehydrostrempeliopine, were completed from a late‐stage divergent intermediate. The synthesis took advantage of efficient nitro‐group reactions with the A/B/C ring skeleton constructed concisely on a gram scale through an asymmetric Michael addition, nitro‐Mannich/lactamisation, Tsuji–Trost allylation, and intramolecular C?N coupling reaction. Other key features of the synthesis are a novel [1,4] hydride transfer/Mannich‐type cyclisation to build ring E and a diastereoselective ring‐closing metathesis reaction to construct ring D. This approach gave access to a late‐stage C14,C15 alkene divergent intermediate that could be simply transformed into (+)‐vallesamidine, (+)‐14,15‐dehydrostrempeliopine, and potentially other schizozygine alkaloids and unnatural derivatives.     

Synthesis of Chiral Tertiary Boronic Esters by Oxime‐Directed Catalytic Asymmetric Hydroboration

Chiral boronic esters are useful intermediates in asymmetric synthesis. We have previously shown that carbonyl‐directed catalytic asymmetric hydroboration (CAHB) is an efficient approach to the synthesis of functionalized primary and secondary chiral boronic esters. We now report that the oxime‐directed CAHB of alkyl‐substituted methylidene and trisubstituted alkene substrates by pinacolborane (pinBH) affords oxime‐containing chiral tertiary boronic esters with yields up to 87 % and enantiomeric ratios up to 96:4 e.r. The utility of the method is demonstrated by the formation of chiral diols and O‐substituted hydroxylamines, the generation of quaternary carbon stereocenters through carbon–carbon coupling reactions, and the preparation of chiral 3,4,4‐trisubstituted isoxazolines.     

Copper‐Catalyzed Enantioselective Construction of Tertiary Propargylic Sulfones

Tertiary propargylic sulfones are of significant importance in organic synthesis and medicinal chemistry, but to date no general asymmetric synthesis approach has been developed. We disclose a versatile copper‐catalyzed sulfonylation of propargylic cyclic carbonates using sodium sulfinates that allows the construction of propargylic sulfones featuring elusive quaternary stereocenters. This method provides the first successful example of such an enantioselective propargylic sulfonylation, features high asymmetric induction, wide functional group tolerance, and scalability, and enables attractive product diversification.     

Asymmetric Total Syntheses of the Akuammiline Alkaloids (−)‐Strictamine and (−)‐Rhazinoline

Strictamine and rhazinoline are representative methanoquinolizidine‐containing akuammiline alkaloids that possess different stereochemistry at the C16 position. A unified approach to the enantioselective total syntheses of these two molecules is described. The key steps in this synthesis include a photocatalytic intra/intermolecular type II radical cascade reaction, a Tsuji–Trost allylation, a palladium‐ or nickel‐mediated cyclization, and a late‐stage intramolecular N‐alkylation reaction.     

Palladium‐Catalyzed Asymmetric [4+3] Cyclization of Trimethylenemethane: Regio‐, Diastereo‐, and Enantioselective Construction of Benzofuro[3,2‐b]azepine Skeletons

The palladium‐catalyzed asymmetric [4+3] cyclization of trimethylenemethane donors with benzofuran‐derived azadienes furnishes chiral benzofuro[3,2‐b]azepine frameworks in high yields (up to 98 %) with exclusive regioselectivities and excellent stereoselectivities (up to >20:1 d.r., >99 % ee). This catalytic asymmetric [4+3] cyclization of Pd‐trimethylenemethane can enrich the arsenal of Pd‐TMM reactions in organic synthesis. In addition, this strategy provides an alternative approach to chiral azepines by a transition‐metal‐catalyzed asymmetric [4+3] cyclization.     

Asymmetric Brønsted Acid Catalyzed Synthesis of Triarylmethanes—Construction of Communesin and Spiroindoline Scaffolds

Aza‐ortho‐quinone methides allow the straightforward asymmetric synthesis of natural‐product‐inspired indole scaffolds possessing a quaternary stereocenter. Our approach provides access to diverse communesin and spiroindoline derivatives with high enantioselectivity under mild reaction conditions. Predictable substitution patterns are found to be the key to our regiodivergent protocols.     

Stochastic aspects of asymmetric autocatalysis and absolute asymmetric synthesis

The main goal of the present review is to collect in a unified framework the deterministic and stochastic models of emergence and amplification of chirality by mechanisms such as asymmetric autocatalysis and absolute asymmetric synthesis. Empirical approach and modeling have recently provided a good insight into these phenomena. Our groups in Italy and Hungary have a wide variety of expertise both in fields of experiments and modeling. In the last decade important results have been achieved, however, more experiments and more detailed deterministic and stochastic models are needed for a better understanding of details and significance of asymmetric autocatalysis and absolute asymmetric synthesis.     

Organocatalytic Asymmetric Cascade Reactions of 7‐Vinylindoles: Diastereo‐ and Enantioselective Synthesis of C7‐Functionalized Indoles

The first catalytic asymmetric cascade reaction of 7‐vinylindoles has been established by the rational design of such substrates. Cascade reactions with isatin‐derived 3‐indolylmethanols in the presence of a chiral phosphoric acid derivative allow the diastereo‐ and enantioselective synthesis of C7‐functionalized indoles as well as the construction of cyclopenta[b]indole and spirooxindole frameworks (all >95:5 d.r., 94–>99 % ee). This approach not only addresses the great challenge of the catalytic asymmetric synthesis of C7‐functionalized indoles, but also provides an efficient method for constructing biologically important cyclopenta[b]indole and spirooxindole scaffolds with excellent optical purity. Investigation of the reaction pathway and activation mode has suggested that this cascade reaction proceeds through a vinylogous Michael addition/Friedel–Crafts process, in which dual H‐bonding activation of the two reactants plays a crucial role.     

Palladium‐Catalzyed Atroposelective 16‐Membered Macrocyclization: Total Synthesis of Isoplagiochin D†

Isoplagiochin D is a ring‐strained macrocyclic bisbibenzylis, which showed stable axial chirality in one biaryl structure, and semistable axial chirality in the other biaryl moiety. We reported here an unprecedented example for the catalytically asymmetric synthesis of ring‐strained atropisomers via Pd‐catalyzed macrocyclization between benzyl halides and carbenes. This newly developed Pd‐catalyzed asymmetric macrocyclization protocol enabled us a quick synthesis of isoplagiochin D in a highly enantioselective manner.     

Atroposelective Synthesis of 3,3’‐Bisindoles Bearing Axial and Central Chirality: Using Isatin‐Derived Imines as Electrophiles

An atroposelective synthesis of a new class of 3,3’‐bisindoles bearing axial and central chirality has been established via catalytic asymmetric addition reactions using isatin‐derived imines as electrophiles (23 examples, up to 80% yield, > 95 : 5 dr, 98 : 2 er). This approach takes advantage of chiral phosphoric acid‐catalyzed dynamic kinetic resolution of 2‐substituted 3,3’‐bisindoles via nucleophilic addition of such substrates with isatin‐derived imines. In this approach, isatin‐derived imines acted as a class of competent electrophiles due to their high reactivity and bulky size, which provided an easy access to axially chiral 3,3'‐bisindoles incorporated with a biologically important chiral 3‐aminooxindole unit. This approach has greatly expanded the generality and applicability of the strategy of dynamic kinetic resolution for the synthesis of enantioenriched 3,3’‐bisindole derivatives bearing both axial and central chirality.     

Catalytic Asymmetric Synthesis of α‐Arylpyrrolidines and Benzo‐fused Nitrogen Heterocycles

Herein, we report a practical two‐step synthetic route to α‐arylpyrrolidines through Suzuki–Miyaura cross‐coupling and enantioselective copper‐catalyzed intramolecular hydroamination reactions. The excellent stereoselectivity and broad scope for the transformation of substrates with pharmaceutically relevant heteroarenes render this method a practical and versatile approach for pyrrolidine synthesis. Additionally, this intramolecular hydroamination strategy facilitates the asymmetric synthesis of tetrahydroisoquinolines and medium‐ring dibenzo‐fused nitrogen heterocycles.     

Enantioselective Rhodium‐Catalyzed Dearomative Arylation or Alkenylation of Quinolinium Salts

A highly enantioselective rhodium(I)‐catalyzed dearomative arylation or alkenylation of easily available N‐alkylquinolinium salts is reported, thus providing an effective and practical approach to the synthesis of dihydroquinolines in up to 99 % ee. This reaction tolerates a wide range of functional groups with respect to both the organic boronic acids and the quinoline starting materials. Moreover, the synthetic utility of this protocol is demonstrated in the formal asymmetric synthesis of bioactive tetrahydroquinoline and the total syntheses of (?)‐angustureine and (+)‐cuspareine.     

Copper(I)‐Catalyzed Asymmetric Dearomatization of Indole Acetamides with 3‐Indolylphenyliodonium Salts

The rapid and direct asymmetric synthesis of 3‐(3a‐indolyl)hexahydropyrroloindoline motifs is an extremely important part of the total synthesis of several alkaloid structures. Herein, an intermolecular, asymmetric cascade dearomatization reaction of indole acetamides with 3‐indolylphenyliodonium salts has been developed. This protocol provides a straightforward access to 3‐(3a‐indolyl)hexahydropyrroloindolines bearing an all‐carbon quaternary stereocenter at the C3 position of the indoline ring with high enantioselectivities. The utility of the protocol has been demonstrated by the formal asymmetric synthesis of folicanthine.     

Copper‐Catalyzed Synthesis of γ‐Amino Acids Featuring Quaternary Stereocenters

The first general asymmetric synthesis of γ,γ‐disubstituted γ‐amino acids by copper‐catalyzed ring opening of nonstrained lactones with amines is reported. This approach features ample scope, operational simplicity, and wide functional‐group diversity. The catalytic process allows access to a series of highly functionalized enantioenriched γ‐amino acids featuring quaternary stereocenters with excellent enantiomeric ratios of up to 98:2 and excellent yields of up to 98 %.