A 4‐Hydroxypyrrolidine‐Catalyzed Mannich Reaction of Aldehydes: Control of anti‐Selectivity by Hydrogen Bonding Assisted by Brønsted Acids

An anti‐selective Mannich reaction of aldehydes with N‐sulfonyl imines has been developed by using a 4‐hydroxypyrrolidine in combination with an external Brønsted acid. The catalyst design is based on three elements: the α‐substituent of the pyrrolidine, the 4‐hydroxy group, and the Brønsted acid, the combination of which is essential for high chemical and stereochemical efficiency. The reaction works with aromatic aldehyde‐derived imines, which have rarely been employed in previously reported enamine‐based anti‐Mannich reactions. Additionally, both N‐tosyl and N‐nosyl imines can be successfully used and the Mannich adducts can be easily reduced or oxidized, and after N‐deprotection the corresponding β‐amino acids and β‐amino alcohols can be obtained with good yields. The results also show that this ternary catalytic system may be practical in other enamine‐based reactions.     

Direct Catalytic Asymmetric Mannich‐Type Reaction of α‐N3 Amide

An α‐N₃ 7‐azaindoline amide serves as a latent enolate to directly engage in an asymmetric Mannich‐type reaction with N‐thiophosphinoyl imines by the action of a cooperative catalyst. The thus‐obtained highly enantioenriched anti‐adduct was transformed into β‐amino‐α‐azido acid in high yield by simple acidic treatment.     

Enantioselective Zinc/BINOL‐Catalysed Alkynylation of Aldimines Generated in Situ from α‐Amido Sulfones

Chiral nonracemic N‐Cbz‐protected propargylic amines have been prepared by the addition of terminal alkynes to imines generated in situ from α‐amido sulfones in the presence of diethylzinc and BINOL‐type ligands as catalysts. The reactions give good yields and high enantioselectivities (ee values up to 95 %) for a good number of aromatic and heteroaromatic α‐amido sulfones and alkynes.     

Organocatalytic Nucleophilic Addition of Hydrazones to Imines: Synthesis of Enantioenriched Vicinal Diamines

In the presence of a catalytic amount of chiral phosphoric acid, nucleophilic addition of N ‐monosubstituted hydrazones to N ‐Boc imines affords differentially protected vicinal diamines in the form of β‐amino N ,N ′‐dialkyldiazenes in excellent yields with high chemo‐, diastereo‐, and enantioselectivity. This catalytic asymmetric aza‐Mannich reaction represents the first example in which N ‐alkyl hydrazones serve as α‐azo carbanion equivalents to provide vicinal diamines with control of the two contiguous stereocenters. The adducts are readily converted into the monoprotected or free diamines and derivatives thereof.     

Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)‐Sitagliptin

In this study, dithiomalonates (DTMs) were demonstrated to be exceptionally efficient Mannich donors in terms of reactivity and stereoselectivity in cinchona‐based‐squaramide‐catalyzed enantioselective Mannich reactions of diverse imines or α‐amidosulfones as imine surrogates. Owing to the superior reactivity of DTMs as compared to conventional malonates, the catalyst loading could be reduced to 0.1 mol % without the erosion of enantioselectivity (up to 99 % ee). Furthermore, by the use of a DTM, even some highly challenging primary alkyl α‐amidosulfones were smoothly converted into the desired adducts with excellent enantioselectivity (up to 97 % ee), whereas the use of a malonate or monothiomalonate resulted in no reaction under identical conditions. The synthetic utility of the chiral Mannich adducts obtained from primary alkyl substrates was highlighted by the organocatalytic, coupling‐reagent‐free synthesis of the antidiabetic drug (?)‐(R)‐sitagliptin.     

A Powerful Chiral Phosphoric Acid Catalyst for Enantioselective Mukaiyama–Mannich Reactions

A new BINOL‐derived chiral phosphoric acid bearing 2,4,6‐trimethyl‐3,5‐dinitrophenyl substituents at the 3,3′‐positions was developed. The utility of this chiral phosphoric acid is demonstrated by a highly enantioselective (ee up to >99 %) and diastereoselective (syn/anti up to >99:1) asymmetric Mukaiyama–Mannich reaction of imines with a wide range of ketene silyl acetals. Moreover, this method was successfully applied to the construction of vicinal tertiary and quaternary stereogenic centers with excellent diastereo‐ and enantioselectivity. Significantly, BINOL‐derived N‐triflyl phosphoramide constitutes a complementary catalyst system that allows the title reaction to be applied to more challenging imines without an N‐(2‐hydroxyphenyl) moiety.     

Chiral Bis(imidazolidine)‐Derived NCN Pincer Rh Complex for Catalytic Asymmetric Mannich Reaction of Malononitrile with N‐Boc Imines

Chiral bis(imidazolidine)‐derived NCN–rhodium complexes ([PhBidine‐RhX₂] and [tBu‐PhBidine‐RhX₂]) were prepared by a C?H insertion method, and the structures were unequivocally determined by X‐ray crystallographic analysis. The [tBu‐PhBidine‐Rh(OAc)₂] complex smoothly catalyzed an asymmetric Mannich reaction of malononitrile with N‐Boc imines to give products in up to 94 % ee, which are useful for the synthesis of chiral α‐amino acids.     

Highly Diastereoselective Synthesis of α‐Difluoromethyl Amines from N‐tert‐Butylsulfinyl Ketimines and Difluoromethyl Phenyl Sulfone

The first highly efficient and stereoselective difluoromethylation of structurally diverse N‐tert‐butylsulfinyl ketimines has been achieved with an in situ generated PhSO₂CF₂^? anion, which provides a powerful synthetic method for the preparation of a variety of structurally diverse homochiral α‐difluoromethyl tertiary carbinamines, including α‐difluoromethyl allylic amines and α‐difluoromethyl propargylamines. The stereocontrol mode of the present diastereoselective difluoromethylation of ketimines was found to be different from that of other known fluoroalkylations of N‐tert‐butylsulfinyl aldimines, which suggests that a cyclic six‐membered transition state may be involved in the reaction.     

Enantioselective and Regiodivergent Functionalization of N‐Allylcarbamates by Mechanistically Divergent Multicatalysis

A pair of mechanistically divergent multicatalytic reaction sequences has been developed consisting of nickel‐catalyzed isomerization of N‐allylcarbamates and subsequent phosphoric‐acid‐catalyzed enantioselective functionalization of the resulting intermediates. By appropriate selection of reaction partners, in situ generated imines and ene‐carbamates are mechanistically partitioned to yield opposing functionalized products. Formal α‐functionalization to give protected α‐arylamines is achieved upon enantioselective Friedel–Crafts reaction with arene nucleophiles, whereas formal β‐functionalization is achieved upon reaction with diarylimine electrophiles in an enantioselective Povarov‐[4+2] cycloaddition.     

Highly Efficient Asymmetric Synthesis of Vinylic Amino Alcohols by Zn‐Promoted Benzoyloxyallylation of Chiral N‐tert‐Butanesulfinyl Imines: Facile and Rapid Access to (−)‐Cytoxazone

An efficient and convenient α‐hydroxyallylation approach for the asymmetric synthesis of a variety of β‐amino‐α‐vinyl alcohols has been successfully developed. A wide range of vinylic amino alcohol derivatives could be obtained in very good yields and with excellent diastereomeric ratios of up to 99:1 in favor of anti isomers by highly diastereoselective Zn‐promoted benzoyloxyallylation of chiral N‐tert‐butanesulfinyl imines with 3‐bromopropenyl benzoate at room temperature. In particular, excellent enantioinduction of the two new stereogenic centers was observed, with up to 98 % ee. The method provides a new route for the direct α‐hydroxyallylation of imines in a highly stereoselective manner. Moreover, the synthetic value of the method has also been demonstrated by the most concise and straightforward synthesis of (?)‐cytoxazone yet reported.     

NIS‐Assisted Aza‐Friedel–Crafts Reaction with α‐Carbamoysulfides as Precursors of N‐Carbamoylimines

A general and practical N‐iodosuccinimide (NIS)‐promoted aza‐Friedel–Crafts reaction of various aromatic nucleophiles with N‐acylimines generated in situ from α‐amidosulfides to give a rapid access to highly functionalized amines is described. The newly developed methodology is very mild, fast, efficient, and complementary.     

Umpolung Reactions of α‐Imino Esters: Useful Methods for the Preparation of α‐Amino Acid Frameworks

This paper summarizes our recent efforts toward the development of tandem reactions utilizing umpolung reactions of α‐imino esters. A highly diastereoselective tandem N‐alkylation–Mannich reaction of α‐imino esters was developed. A tandem N‐alkylation–addition reaction of α‐imino esters derived from ethyl glyoxylate with various aldehydes proceeded to give 1,2‐amino alcohols. The same reaction also proceeded efficiently using a novel flow system comprising two connected microreactors. Novel syntheses of α‐quaternary alkynyl amino esters and allenoates were developed through the use of umpolung N‐addition to β,γ‐alkynyl α‐imino esters, followed by regioselective acylation. In addition, a highly regioselective tandem N‐alkylation–vinylogous aldol reaction of β,γ‐alkenyl α‐imino esters was discovered. N‐Alkylation of α‐iminophosphonates followed by a Horner–Wadsworth–Emmons reaction with aldehydes occurred to afford enamines, which can be used in a four‐component coupling reaction with methyl vinyl ketone. α‐N‐Acyloxyimino esters served as highly efficient substrates for the N,N,C‐trialkylation reaction to introduce various nucleophiles at the imino nitrogen and carbon atoms.     

Catalytic Asymmetric Phase‐Transfer Michael Reaction and Mannich‐Type Reaction of Glycine Schiff Bases with Tartrate‐Derived Diammonium Salts

Catalytic asymmetric Michael and Mannich‐type reactions of glycine Schiff bases with chiral two‐center organocatalysts, tartrate‐derived diammonium salts (TaDiASs), are described. On the basis of conformational studies, optimized TaDiASs with a 2,6‐disubstituted cyclohexane spiroacetal were newly designed. These TaDiASs catalyzed the asymmetric Michael and Mannich‐type reactions of glycine Schiff bases with higher enantioselectivity than previous catalysts. In the Mannich‐type reaction, aromatic N‐Boc‐protected imines (Boc=tert‐butoxycarbonyl) as well as enolizable alkyl imines were applicable. As a synthetic application of the catalytic asymmetric Mannich‐type reaction with the optimized TaDiASs, we developed a catalytic asymmetric total synthesis of (+)‐nemonapride, which is an antipsychotic agent.     

Enantioselective Construction of Vicinal Tetrasubstituted Stereocenters by the Mannich Reaction of Silyl Ketene Imines with Isatin‐Derived Ketimines

A highly enantioselective Mannich reaction of silyl ketene imines with isatin‐derived ketimines has been realized by using a chiral N,N′‐dioxide/Zn^II catalyst. A variety of β‐amino nitriles containing congested vicinal tetrasubstituted stereocenters were obtained with excellent outcomes (up to 98 % yield, >19:1 d.r. and 99 % ee). Based on the experimental investigations, a possible transition state has been proposed to explain the origin of the asymmetric induction.     

Sterically Hindered and Deconjugative α-Regioselective Asymmetric Mannich Reaction of Meinwald Rearrangement-Intermediate

Compared to γ-addition, the α-addition of α-branched β,γ-unsaturated aldehydes faces larger steric hindrance and disrupts the π–π conjugation, which might be why very few examples are reported. In this article, a highly diastereo- and enantioselective α-regioselective Mannich reaction of isatin-derived ketimines with α-, β- or γ-branched β,γ-unsaturated aldehydes, generated in situ from Meinwald rearrangement of vinyl epoxides, is realized by using chiral N,N′-dioxide/Sc^III catalysts. A series of chiral α-quaternary allyl aldehydes and homoallylic alcohols with vicinal multisubstituted stereocenters are constructed in excellent yields, good d.r. and excellent ee values. Experimental studies and DFT (density functional theory) calculations reveal that the large steric hindrance of the ligand and the Boc (tButyloxy carbonyl) protecting group of imines are critical factors for the α-regioselectivity.     

Chiral Ammonium Betaine‐Catalyzed Highly Stereoselective Aza‐Henry Reaction of α‐Aryl Nitromethanes with Aromatic N‐Boc Imines

A highly stereoselective aza‐Henry reaction of α‐aryl nitromethanes with aromatic N‐Boc imines was established by using C₁‐symmetric chiral ammonium betaine as a bifunctional organic base catalyst. Various substituted aryl groups for both imines and nitromethanes were tolerated in the reaction, and a series of precursors for the synthesis of unsymmetrical anti‐1,2‐diaryl ethylenediamines was provided.     

BINOL Phosphoric Acid‐Catalyzed Asymmetric Mannich Reaction of Cyclic N‐Acyl Ketimines with Cyclic Enones

A highly enantio‐ and diastereoselective Mannich reaction of cyclic N‐acyl ketimines generated in situ from 3‐hydroxyisoindolin‐1‐ones with cyclic enones has been accomplished using a chiral phosphoric acid catalyst to afford the chiral isoindalinone derivatives in high yields with excellent enantioselectivities (upto 97 % ee). This is the first report on the synthesis of chiral isoindolin‐1‐ones bearing adjacent quaternary and tertiary stereogenic centers.     

Asymmetric Ring Opening/Cyclization/Retro‐Mannich Reaction of Cyclopropyl Ketones with Aryl 1,2‐Diamines for the Synthesis of Benzimidazole Derivatives

A highly efficient asymmetric ring‐opening/cyclization/retro‐Mannich reaction of cyclopropyl ketones with aryl 1,2‐diamines has been realized using a chiral N,N′‐dioxide/Sc^III catalyst. Benzimidazoles containing chiral side chains were generated under mild reaction conditions in excellent outcomes (up to 99 % yield and 97 % ee). This method also provides efficient access to chiral benzimidazole‐substituted amide and cycloheptene derivatives.     

Brønsted Acid Catalyzed Addition of Enamides to ortho‐Quinone Methide Imines—An Efficient and Highly Enantioselective Synthesis of Chiral Tetrahydroacridines

The direct and highly enantioselective synthesis of tetrahydroacridines was achieved through the phosphoric acid catalyzed addition of enamides to in situ generated ortho‐quinone methide imines and subsequent elimination. This novel one‐step process constitutes a very efficient, elegant, and selective synthetic approach to valuable N‐heterocycles with a 1,4‐dihydroquinoline motif. By subsequent highly diastereoselective hydrogenation and N‐deprotection the reaction products were easily converted into free hexahydroacridines with a total of three new stereogenic centers.     

Total Synthesis of (−)‐Vindorosine

Outlined herein is a novel and scalable synthesis of (−)‐vindorosine based on two key transformations. A highly diastereoselective vinylogous Mannich addition of dioxinone‐derived lithium dienolates with indolyl N ‐tert‐butanesulfinyl imines has been developed. In addition, an intramolecular Heathcock/aza‐Prins cyclization was introduced to construct both the C, and the highly substituted E rings for the synthesis of (−)‐vindorosine and related alkaloids.