Organocatalytically Enantioselective Approach to Polysubstituted Tetrahydropyridines and Piperidines

A convenient and highly enantioselective method for assembly of functionalized 1,2,3,4,5‐pentasubstituted tetrahydropyridines and piperidines was developed. This method relies on preparing the required enantiopure cyclic semi‐acetals via an organocatalyzed Michael addition/cyclization cascade reaction of aldehydes and α‐keto‐α,β‐unsaturated esters, and subsequent reductive amination/condensation with primary amines.     

Tetrahydropyridinediols and related aldehydes from the reactions of pyridine N-oxide with mercaptans

A new series of tetrahydropyridines was isolated when 1-adamantyl or t-butyl mercaptan was added last to a solution of pyridine N-oxide and triethylamine in acetic anhydride. Under these conditions, the predominant tetrahydropyridines proved to be 1-acetyl-2-alkylthio-3-acetoxy-6-hydroxy-1,2,3,6-tetrahydropyridines. These carbinolamides were isomerized in part during silica gel column chromatography to trans-4-acetoxy-5-alkylthio-5-acetamido-2-pentenals.     

Synthesis of N‐(substituted phenylcarbonylamino)‐4‐ethyl‐1,2,3,6‐tetrahydropyridines as potential nonsteroidal anti‐inflammatory agents

Fourteen novel N‐(substituted phenylcarbonylamino)‐4‐ethyl‐1,2,3,6‐tetrahydropyridines 9 were synthesized in fair to good yields. 4‐Ethylpyridine 5 reacted with O‐mesitylenesulfonylhydroxylamine (O‐MSH) 4 to furnish N‐amino‐4‐ethylpyridinium mesitylenesulfonate 6 . The reaction of 6 with substituted acid chlorides 7 gave the stable crystalline pyridinium ylides 8a‐8n . A sodium borohydride reduction of 8 in absolute ethanol furnished the target compounds N‐(substituted phenylcarbonylamino)‐4‐ethyl‐1,2,3,6‐tetrahydropyridines 9a‐9n .     

Benzomorphan related compounds. XIV. Synthesis of 2-(2-pyrrolylmethyl)- and 2-(2-indolylmethyl)tetrahydropyridines and cyclization to pyrrolo[3,2-f]morphans

The synthesis of 2-{2-pyrrolylmethyl)- and 2-(2-indolylmethyl)tetrahydropyridines by condensation of 2-cyanopyridines with appropriate pyrrole or indole derivatives followed by ketone reduction, quaternization and sodium borohydride reduction are described. The acid-induced cyclization of 2-(2-pyrrolylmethyl)tetrahydropyridines affords 4,5,6,7,8,9-hexahydro-4,8-methanopyrrolo[2,3-d]azocine systems (pyrrolo[3,2-f]-morphans), although the method fails with N-benzyl substituted pyrroles. The acid treatment of 2-(2-indolylmethyl)tetrahydropyridines and of 2-indolyl tetrahydro-2-pyridyl ketones is not a suitable procedure for the preparation of indolo[3,2-f]morphans, because of the protonation of indole nucleus or carbonyl group, respectively.     

A Valuable Synthetic Route to the Enantiopure Functionalized N-Substituted Aziridines

Chiral butyrolacto[3,4-b]-2(S)-6(R)-1-N-akylaziridines 7 were synthesized in enantiopure form utilizing racemic 5-methoxy-3-bromo-2(5H)-furanone (5) and available amines (6) as key precursors. After highly effective reduction of 7, the functionaiized 2(S),3(R)-dihyroxymethyl-N-alkylaziridines (8) were obtained in good yields with ≥98% ee. This is a simple and pratical method for the preparation of enantiopure aziridines which are important intermediates in the synthesis of biologic active molecules.     

Organocatalytic Enantioselective Oxidative C?H Alkenylation and Arylation of N‐Carbamoyl Tetrahydropyridines and Tetrahydro‐β‐carbolines

The first organocatalytic enantioselective C H alkenylation and arylation reactions of N‐carbamoyl tetrahydropyridines and tetrahydro‐β‐carbolines (THCs) are described. The metal‐free processes represent an efficient and straightforward approach to a variety of structurally and electronically diverse α‐substituted tetrahydropyridines and THCs in good yields with excellent regio‐ and enantioselectivities. Preliminary control experiments provide important insights into the reaction mechanism.     

Organocatalytic Enantioselective Oxidative CH Alkenylation and Arylation of N‐Carbamoyl Tetrahydropyridines and Tetrahydro‐β‐carbolines

The first organocatalytic enantioselective C? H alkenylation and arylation reactions of N‐carbamoyl tetrahydropyridines and tetrahydro‐β‐carbolines (THCs) are described. The metal‐free processes represent an efficient and straightforward approach to a variety of structurally and electronically diverse α‐substituted tetrahydropyridines and THCs in good yields with excellent regio‐ and enantioselectivities. Preliminary control experiments provide important insights into the reaction mechanism.     

Phosphine‐Catalyzed [4+2] Cycloadditions of Allenic Ketones: Enantioselective Synthesis of Functionalized Tetrahydropyridines

Amino‐acid‐derived phosphine catalyzed [4+2] cycloaddition leading to chiral tetrahydropyridines, making use of α‐substituted allenic ketones as “C4 synthons” and N‐sulfonyl cyclic ketimines, has been developed. This asymmetric cycloaddition tolerates a wide range of α‐substituted allenic ketones. A series of chiral sultam‐fused tetrahydropyridines bearing a quaternary stereocenter were obtained in high yields with good enantioselectivities.     

Addition reactions of 1,1,1-trifluoro-4-trimethylstannylbut-3-yn-2-one and 1,1,1-trifluorobut-3-yn-2-one to some tetrahydropyridines. Synthesis of trifluoroacylated polysubstituted tetrahydroazocines

A reaction of tetrahydropyridines, obtained by the Diels-Alder reaction from α,β-unsat-urated N,N-dimethylhydrazones and methyl acrylate, with acetylenes activated with the trifluoroacetyl group has been studied and found to lead to polysubstituted trifluoroacylated tetrahydroazocines. No cyclobutene intermediates have been detected.     

Asymmetric synthesis of di- and trisubstituted pyrrolidinones via zirconium-mediated intramolecular coupling of N-3-alkenyl carbamates

N-3-Alkenyl carbamates, which are readily available in enantiomerically pure form, undergo a stereoselective intramolecular coupling under the effect of a Cp₂ZrCl₂/2n-BuLi reagent. The influence of the carbamate structure on the stereoselectivity was tested. The reaction gives an easy access to various di- and trisubstituted enantiopure pyrrolidinones.     

Dual Palladium(II)/Tertiary Amine Catalysis for Asymmetric Regioselective Rearrangements of Allylic Carbamates

The streamlined catalytic access to enantiopure allylic amines as valuable precursors towards chiral β‐ and γ‐aminoalcohols as well as α‐ and β‐aminoacids is desirable for industrial purposes. In this article an enantioselective method is described that transforms achiral allylic alcohols and N‐tosylisocyanate in a single step into highly enantioenriched N‐tosyl protected allylic amines via an allylic carbamate intermediate. The latter is likely to undergo a cyclisation‐induced [3,3]‐rearrangement catalysed by a planar chiral pentaphenylferrocene palladacycle in cooperation with a tertiary amine base. The otherwise often indispensable activation of palladacycle catalysts by a silver salt is not required in the present case and there is also no need for an inert gas atmosphere. To further improve the synthetic value, the rearrangement was used to form dimethylaminosulfonyl‐protected allylic amines, which can be deprotected under non‐reductive conditions.     

Absolute Asymmetric Synthesis of Enantiopure Organozinc Reagents,Followed by Highly Enantioselective Chlorination

We report the absolute asymmetric synthesis (AAS) of indenylzinc reagents by using total spontaneous resolution followed by enantiospecific conversion into 1‐chloroindene. The chiral complex [Zn(dcp)(ind)(tmeda)] (dcp=2,6‐dichlorophenoxy and tmeda=N,N,N′,N′‐tetramethylethylenediamine) ( 3 ) was prepared from the achiral starting materials indene, potassium, zinc chloride, TMEDA, and 2,6‐dichlorophenol. The reagent resolved spontaneously on crystallization, and single crystals of 3 react with N‐chlorosuccinimide in the presence of benzoquinone in 2‐propanol to give 1‐chloroindene in >98 % enantiomeric excess. It was found that (R)‐ 3 gave (R)‐1‐chloroindene upon reaction, indicating an S_E2′‐mechanism. Since bulk samples of 3 gave optically active product upon chlorination, total spontaneous resolution must have occurred. This demonstrates that enantiopure products can be obtained through the absolute asymmetric synthesis of organometallic reagents starting from achiral materials. The general absolute asymmetric synthesis (AAS) method offers easy access to both enantiomers and an almost limitless variation in the design of the product.     

Novel Asymmetric Formylation of Aromatic Compounds: Enantioselective Synthesis of Formyl 7,8‐Dipropyltetrathia[7]helicenes

Asymmetric formylation of aromatic compounds is virtually unexplored. We report the synthesis and evaluation of a library including 20 new chiral formamides in the kinetic resolution of 7,8‐dipropyltetrathia[7]helicene, affording the corresponding formyl‐ or diformylhelicenes in up to 73 % ee, making enantiopure compounds available by recrystallisation. With the N,N‐disubstituted formamides used in this study, the best enantioselectivity has been achieved with R¹=iPr, R²=Me, R³=H, R⁴=1‐naphthyl or its 1‐pyrenyl equivalent.     

Asymmetrized tris(hydroxymethyl)methane as precursor of iminosugars: application to the synthesis of isofagomine

A new synthetic application of asymmetrized tris(hydroxymethyl)methane (THYM*), readily obtained in both enantiomeric forms through a chemoenzymatic procedure, is reported. In this case THYM* precursor 3 was elaborated by ring closing metathesis into some enantiopure branched tetrahydropyridines, that have been used as precursors of the potent glycosidase inhibitor isofagomine28.     

Access to Enantioenriched Spiro-ϵ-Lactam Oxindoles by an N-Heterocyclic Carbene-Catalyzed [4+3] Annulation of Flexible Oxotryptamines with Enals

Oxotryptamines were firstly used as flexible four-atom synthons in an NHC-catalyzed formal [4+3] annulation, providing a novel enantioselective method to access structurally diverse spiro-ϵ-lactam oxindoles with excellent enantioselectivities. This metal-free reaction features a broad substrate scope, excellent functional-group tolerance and proceeds under mild reaction conditions. Importantly, enantiopure privileged hexahydropyrroloindoles could be easily constructed by a one-pot process from the resulting spiro-ϵ-lactam oxindoles.     

Asymmetric and Geometry‐Selective α‐Alkenylation of α‐Amino Acids

Both E‐ and Z‐N′‐alkenyl urea derivatives of imidazolidinones may be formed selectively from enantiopure α‐amino acids. Generation of their enolate derivatives in the presence of K⁺ and [18]crown‐6 induces intramolecular migration of the alkenyl group from N′ to Cα with retention of double bond geometry. DFT calculations indicate a partially concerted substitution mechanism. Hydrolysis of the enantiopure products under acid conditions reveals quaternary α‐alkenyl amino acids with stereodivergent control of both absolute configuration and double bond geometry.     

Synthesis of Polycyclic Tertiary Carbinamines by Samarium Diiodide Mediated Cyclizations of Indolyl Sulfinyl Imines

Samarium diiodide mediated cyclizations of N‐acylated indole derivatives bearing sulfinyl imine moieties afforded polycyclic tertiary carbinamines with moderate to excellent diastereoselectivities. Lithium bromide and water turned out to be the best additives to achieve these transformations in good yields. Using enantiopure sulfinyl imines the outcome strongly depends on the reactivity of the indole moiety. Whereas with unactivated indole derivatives desulfinylation and formation of racemic products was observed, indoles bearing electron‐withdrawing substituents at C‐3 afforded the polycyclic products with intact N‐sulfinyl groups and with excellent diastereoselectivity, finally allowing the preparation of enantiopure tertiary carbinamines. The mechanisms of these processes are discussed.     

Stereocontrolled Oxidative Additions upon 1,4-Dihydropyridines: Synthesis of Hexahydrofuro[2,3-b]pyridine and Hexahydropyrano[2,3-b]pyridine Derivatives

trans-α-Alkoxy-β-halotetrahydropyridines are synthesized in a very efficient single step by stereocontrolled N-halosuccinimide (NXS)–promoted alcohol addition to the enamine group in N-alkyl-1,4-dihydropyridines. These compounds are cyclized using sodium cyanoborohydride in the presence of 2,2′-azobis(2-methylpropionitrile), azabisisobutyronitrile (AIBN) (cat.), and tributylstannane (cat.), affording hexahydrofuro[2,3-b]pyridine and hexahydropyrano[2,3-b]pyridine derivatives. The cyclized product undergoes ring-opening reaction by a nucleophile in the presence of Lewis acid to afford highly functionalized tetrahydropyridines.     

Enantiospecific access to 10-N-substituted camphors

A general and straightforward enantiospecific access to synthetically valuable 10-N-substituted camphors (amines and secondary amides) has been developed. The synthetic method uses camphor as the starting enantiopure material and takes place in five individual steps with a high overall yield. The process involves a stereocontrolled double-Wagner-Meerwein-rearrangement strategy to generate key-intermediate 10-(triflyloxy)camphor, a peculiar and highly-reactive primary triflate, which is able to alkylate soft N-nucleophiles, such as amines and nitriles, easily and without producing Grob-like fragmentation of the β-(triflyloxy)ketone-based norbornane system.     

Tandem enantioselective conjugate addition-Mannich reactions: efficient multicomponent assembly of dialkylzincs, cyclic enones and chiral N-sulfinimines

A convenient access to enantiopure β-amino ketones through a multicomponent reaction of dialkyl zinc reagents, cyclic enones and chiral N-tert-butanesulfinimines is disclosed. Four diastereoisomers can be selectively obtained by the appropriate choice of the chiral ligand (L or ent-L) and the chiral N-sulfinimine (R_S or S_S). The protocol is particularly efficient when enolisable N-sulfinimines are used.