Cyclization of Zincated α‐N‐Homoallylamino Nitriles: A New Entry to Enantiopure 2,3‐Methanopyrrolidines

Stereoselective cyclization of zincated α‐N‐homoallylamino nitriles has been developed. Following treatment with lithium diisopropylamide (LDA) and transmetalation with zinc bromide, α‐N‐(1‐phenylethyl)‐N‐homoallylamino nitriles lead to 2,3‐methanopyrrolidines in moderate to good yields (up to 66 %) and excellent selectivities (up to >98:2). With substrates derived from α‐branched homoallylic amines, a stereospecific inversion of the homoallylic stereogenic center was observed. To account for this, a mechanistic rationale involving the formation of zincioiminium ions from zincated α‐amino nitriles is put forward. 2,3‐Methanopyrrolidines should then arise from a sequence involving an aza‐Cope rearrangement providing a configurationally stable (2‐azoniaallyl)zinc species that then undergoes a [3+2] cycloaddition reaction.     

Catalytic Enantioselective α‐Ketol Rearrangement

A highly enantioselective α‐ketol rearrangement has been developed. In the presence of a chiral Cu‐bisoxazoline complex, achiral β‐hydroxy‐α‐dicarbonyls were isomerized to chiral α‐hydroxy‐β‐dicarbonyls and their bicyclic derivatives in excellent yields and enantioselectivities. Enantioenriched 2‐acyl‐2‐hydroxy cyclohexan‐1‐ones, dihydroxyhexahydrobenzofuranones, and dihydroxyhexahydro‐cycloheptafuranones, with up to three stereocenters, were readily prepared from achiral starting materials in one operation. The reaction is applicable to the desymmetrization of meso substrates and kinetic resolution of racemic alcohols.     

Enantioselective Catalytic Aldehyde α‐Alkylation/Semipinacol Rearrangement: Construction of α‐Quaternary‐δ‐Carbonyl Cycloketones and Total Synthesis of (+)‐Cerapicol

An enantioselective aldehyde α‐alkylation/semipinacol rearrangement was achieved through organo‐SOMO catalysis. The catalytically generated enamine radical cation serves as a carbon radical electrophile that can stereoselectively add to the alkene of an allylic alcohol and initiate ensuing ring‐expansion of cyclopropanol or cyclobutanol. This tandem reaction enables the production of a wide range of nonracemic functionalizable α‐quaternary‐δ‐carbonyl cycloketones in high yields and excellent enantioselectivity from simple aldehydes and allylic alcohols. As a key step, the intramolecular reaction was also successfully applied in the asymmetric total synthesis of (+)‐cerapicol.     

Gold(I)‐Catalyzed Desymmetrization of 1,4‐Dienes by an Enantioselective Tandem Alkoxylation/Claisen Rearrangement

An enantioselective alkoxylation/Claisen rearrangement reaction was achieved by a strategic desymmetrization of 1,4‐dienes under the catalysis of (S)‐DTBM‐Segphos(AuCl)₂/AgBF₄. This reaction system was highly selective for the formation of 3,3‐rearrangement products, providing cycloheptenes with various substitutions in good yield and good to excellent enantioselectivity. This transformation was further extended to bicyclic ring substrates, providing the opportunity to easily assemble 5,6‐ and 6,7‐fused ring systems.     

Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides

Synthesis of enantiomerically enriched α‐hydroxy amides and β‐amino alcohols has been accomplished by enantioselective reduction of α‐keto amides with hydrosilanes. A series of α‐keto amides were reduced in the presence of chiral Cu^II/(S)‐DTBM‐SEGPHOS catalyst to give the corresponding optically active α‐hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one‐pot complete reduction of both ketone and amide groups of α‐keto amides has been achieved using the same chiral copper catalyst followed by tetra‐n‐butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β‐amino alcohol derivatives.     

tert‐Butyldimethylsilyl‐Directed Highly Enantioselective Approach to Axially Chiral α‐Allenols

A highly efficient and enantioselective synthesis of axially chiral α‐allenols was realized in practical yields with 96–99 % ee or de from TBS‐protected propargylic alcohols, aldehydes, and a commercially available, inexpensive, chiral, secondary amine (S)‐α,α‐diphenylprolinol or its enantiomer followed by desilylation. The easily removable TBS group not only acts as a protecting group, but also as a possible sterically directing group for the excellent enantioselectivity and in situ prevention of possible allene racemization.     

Chemo‐ and Enantioselective Oxidative α‐Azidation of Carbonyl Compounds

We report high‐performance I⁺/H₂O₂ catalysis for the oxidative or decarboxylative oxidative α‐azidation of carbonyl compounds by using sodium azide under biphasic neutral phase‐transfer conditions. To induce higher reactivity especially for the α‐azidation of 1,3‐dicarbonyl compounds, we designed a structurally compact isoindoline‐derived quaternary ammonium iodide catalyst bearing electron‐withdrawing groups. The nonproductive decomposition pathways of I⁺/H₂O₂ catalysis could be suppressed by the use of a catalytic amount of a radical‐trapping agent. This oxidative coupling tolerates a variety of functional groups and could be readily applied to the late‐stage α‐azidation of structurally diverse complex molecules. Moreover, we achieved the enantioselective α‐azidation of 1,3‐dicarbonyl compounds as the first successful example of enantioselective intermolecular oxidative coupling with a chiral hypoiodite catalyst.     

Enantioselective α‐Benzylation of Acyclic Esters Using π‐Extended Electrophiles

The first asymmetric cooperative Lewis base/palladium catalyzed benzylic alkylation of acyclic esters is reported. This reaction proceeds via stereodefined C1‐ammonium enolate nucleophiles. Critical to its success was the identification of benzylic phosphate electrophiles, which were uniquely reactive. Alkylated products were obtained with very high levels of enantioselectivity, and this method has been applied toward the synthesis of the thrombin inhibitor DX‐9065a.     

An Expeditious Access to Enantiomerically Pure cis‐Dialkyl‐Substituted γ‐ and δ‐Lactones

A facile general route to enantiomerically pure 3,4‐cis‐dialkyl‐substituted γ‐lactones and 4,5‐cis‐dialkyl‐substituted δ‐lactones by TiCl₄‐mediated Evans asymmetric aldolization as the key step is exemplified by synthesis of cis‐(3R,4R)‐3‐methyldecan‐4‐olide and (4R,5R)‐aerangis lactone.     

Enantioselective NH Insertion Reaction of α‐Aryl α‐Diazoketones: An Efficient Route to Chiral α‐Aminoketones

A highly enantioselective N? H insertion reaction of α‐diazoketones was developed by using cooperative catalysis by dirhodium(II) carboxylates and chiral spiro phosphoric acids. The insertion reaction provides a new access route to diverse chiral α‐aminoketones, which are versatile building blocks in organic synthesis, with fast reaction rates, good yields and high enantioselectivity under mild and neutral conditions.     

Enantioselective Synthesis of α‐Secondary and α‐Tertiary Piperazin‐2‐ones and Piperazines by Catalytic Asymmetric Allylic Alkylation

The asymmetric palladium‐catalyzed decarboxylative allylic alkylation of differentially N‐protected piperazin‐2‐ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine‐2‐ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.     

Enantioselective Synthesis of Medium‐Sized Lactams via Chiral α,β‐Unsaturated Acylammonium Salts

Medium‐sized lactams are important structural motifs found in a variety of bioactive compounds and natural products but are challenging to prepare, especially in optically active form. A Michael addition/proton transfer/lactamization organocascade process is described that delivers medium‐sized lactams, including azepanones, benzazepinones, azocanones, and benzazocinones, in high enantiopurity through the intermediacy of chiral α,β‐unsaturated acylammonium salts. An unexpected indoline synthesis was also uncovered, and the benzazocinone skeleton was transformed into other complex heterocyclic derivatives, including spiroglutarimides, isoquinolinones, and δ‐lactones.     

Synthesis of 5,6-Dihydrophenanthridine (DHPA) Sulfonamides and Subsequent Acid-Catalyzed Rearrangement to Diaryl Sulfones

Selective method of reduction of the ortho-nitro groups in 2,4,6-trinitrotoluene by hydrazine hydrate in the presence of FeCl₃ and charcoal has been elaborated. This method allows obtaining either 2-amino-4,6-dinitrotoluene or 2,6-diamino-4-nitrotoluene as well as 2,4,6-triaminotoluene from TNT.