Synthesis of 3,4-disubstituted piperidines by carbonyl ene and Prins cyclizations: a switch in diastereoselectivity between Lewis and Brønsted acid catalysts

[reaction: see text] A novel diastereoselective approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 6a-e catalyzed by the Lewis acid methyl aluminum dichloride in refluxing chloroform affords trans piperidines 8a-e with diastereomeric ratios of up to 93:7. By contrast, Prins cyclization of 6a-e catalyzed by hydrochloric acid at low temperatures affords cis products 7a-e with diastereomeric ratios of up to 98:2.     

Synthesis of 3,4-disubstituted piperidines by ene cyclisation of 4-aza-1,7-dienes

Ene cyclisation of a variety of 4-aza-1,7-dienes affords 3,4-disubstituted piperidines. In particular, cyclisation of diesters 14 and 20 catalysed by MeAlCl₂ gives the corresponding trans 3,4-disubstituted piperidines with diastereomeric ratios of >200:1.     

Synthesis of octahydroquinolines through the Lewis acid catalyzed reaction of vinyl allenes and imines

The reaction of vinyl allenes with imines under Lewis acid catalysis has been explored. Vinyl allenes in which the allenic portion of the molecule is tri- or tetrasubstituted gave octahydroquinoline derivatives as single isomers together with a minor compound formed by an ene reaction of the imine with the allene. Compounds in which the allene is 1,3-disubstituted do not react under the conditions assayed.     

Transition-Metal-Free Multiple Functionalization of Piperidines to 4-Substituted and 3,4-Disubstituted 2-Piperidinones

Remote and multiple functionalization of piperidines without the use of transition-metal catalysts and elaborate directing groups is one of the major challenges in organic synthesis. Herein is reported an unprecedented two-step protocol that enables the multiple functionalization of piperidines to either 4-substituted or trans-3,4-disubstituted 2-piperidones. First, by exploiting the duality of TEMPO reactivity, which under oxidative and thermal conditions fluctuates between cationic and persistent-radical form, a novel multiple C(sp³)-H oxidation of piperidines to α,β-unsaturated 2-piperidones was developed. Second, the intrinsic low reactivity of the unsaturated piperidones toward conjugated Grignard additions was overcome by using trimethylsilyl chloride (TMSCl) as Lewis acid. Subsequently, conjugated Grignard addition/electrophilic trapping protocol provided substituted 2-piperidone intermediates, some of which were then transformed into pharmaceutical alkaloids.     

trans-3,4-Disubstituted pyrrolidines by 1,3-dipolar cycloaddition: enantioselective approaches and their limitations

In the presence of a chiral Lewis acid as co-catalyst, the acid-catalysed 1,3-dipolar cycloaddition reaction yielding trans-3,4-disubstituted pyrrolidines from an azomethine ylide and achiral α,β-unsaturated dipolarophiles proceeded with low enantioselectivity. Therefore a number of α,β-unsaturated dipolarophiles linked to chiral auxiliaries were examined as substrates. Camphorsultam was the best auxiliary and gave good diastereoselectivity (dr=74:26). When combining chiral Lewis acids with a dipolarophile linked to a chiral auxiliary, the enantioselectivity could be slightly increased. As judged by ¹³C NMR, the small effect of the chiral Lewis acids on selectivity was probably due to breakdown of the initially formed complex with the dipolarophile caused by the dipole precursor.     

不对称双酸催化3,4-二氢-2H-吡喃的反电子Hetero-Diels-Alder反应

研究了双酸催化剂不对称催化烯醚和β,γ-不饱和α-酮酸酯的反电子Hetero-Diels-Alder (HDA)反应, 为手性合成3,4-二氢-2H-吡喃类化合物提供了一种新的催化合成方法. InBr₃与手性磷酸钙盐Ca(1c)₂组合的手性双路易斯酸催化体系能够有效催化3,4-二氢-2H-吡喃和β,γ-不饱和α-酮酸酯的反电子HDA反应, 反应给出优秀的产率(最高达98%), 中等到良好的非对映选择性(最高达89:11)和良好到优秀的对映选择性(最高可达94%). 并且该双酸催化体系也能成功实现其它烯醚(如: 2,3-二氢-2H-呋喃, 乙烯基乙醚)的HDA反应, 获得优秀的非对映选择性(>94:6)和良好的对映选择性.     

Development of an unusually highly enantioselective hetero-Diels-Alder reaction of benzaldehyde with activated dienes catalyzed by hypercoordinating chiral aluminum complexes

The effect of Lewis acid catalysis of the hetero-Diels-Alder reaction between benzaldehyde and activated dienes (e.g. the Danishefsky's diene) has been investigated. In the present work we decided to study a series of chiral aluminum complexes as potential catalysts for the hetero-Diels-Alder reaction in order to gain a better understanding of the effect on the chiral induction of varying the steric and electronic environment of the metal ion. The results of this study prompted us to conclude that steric effects in the ligand coordination sphere and hypercoordination are strongly contributing factors to the optical yield of the reaction. Optimization of the reaction culminated in the synthesis of the hetero-Diels-Alder product in 99.4% ee and 97% yield of the isolated product. Based on the experimental results the mechanism for the hetero-Diels-Alder reaction is discussed and it is postulated that hypercoordination to the chiral aluminum Lewis acid center is of importance for the reaction.     

Synthesis of 3,4-disubstituted piperidines by carbonyl ene and prins cyclizations: switching between kinetic and thermodynamic control with Brønsted and Lewis acid catalysts

A novel approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 4a-e catalyzed by MeAlCl(2) in refluxing chloroform afforded the trans piperidines 7a-e with diastereomeric ratios of up to 93:7, while aldehyde 4f afforded solely the cis product 6f, which was resistant to isomerization to the trans isomer. It was demonstrated for 4a that the cyclization catalyzed by a variety of Lewis acids at low temperature proceeded under kinetic control to afford predominantly the cis piperidine 6a, and this isomerized to the thermodynamically more stable trans piperidine 7a on warming. In contrast, Prins cyclization of 4a-e catalyzed by concentrated hydrochloric acid in CH2Cl2 at low temperature afforded cis piperidines 6a-e with diastereomeric ratios of up to >98:2. The yield and diastereoselectivity of these cyclizations could be improved by using HCl-saturated CH2Cl2 to form the corresponding chloride, followed by elimination of HCl effected by ammonia. Aldehydes 4f and 4galso cyclized in good yield under the latter conditions. Mechanistic studies supported by DFT calculations (B3LYP/6-31G(d)) suggest that the cyclizations proceed via a mechanism with significant carbocationic character, with the cis carbocation being more stable than the trans carbocation. DFT calculations (B3LYP/6-31G(d)) of the transition state energies for concerted cyclization show that the cis piperidine is also the favored product from cyclization through a more concerted mechanism.     

Hydrogen-bond-promoted hetero-Diels-Alder reactions of unactivated ketones

We report the first examples of hydrogen-bond-promoted acceleration of hetero-Diels-Alder reactions and the use of such catalysis for the hetero-Diels-Alder reactions of simple, unactivated ketones. Several spiro-fused dihydropyans were synthesized in good yields using this procedure. This activation protocol represents an attractive and operationally simple alternative to conventional, Lewis acid catalysis.     

Diastereoselective intermolecular ene reactions: synthesis of 4,5,6,7-tetrahydro-1H-benzo[d]imidazoles

The Diels-Alder cycloadducts of 4-vinylimidazoles and N-phenylmaleimide are shown to undergo facile intermolecular ene reactions. Overall the reaction of three simple molecules (a diene, a dienophile and an enophile) in a two-step process gives 4,5,6,7-tetrahydro-1H-benzo[d]imidazoles with high yields, high atom economy and diastereocontrol of up to 5 new stereocentres.     

A highly enantioselective hetero-Diels-Alder reaction of aldehydes with Danishefsky's diene catalyzed by chiral titanium(IV) 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol complexes

The catalytic effect of chiral Lewis acids on the hetero-Diels-Alder reaction between aldehydes and Danishefsky's diene (1) has been investigated. A variety of combinations of different ligands and Lewis acids have been examined as catalysts for the hetero-Diels-Alder reaction between benzaldehyde and 1, and it has been found that the readily accessible Ti(IV)-H(8)-BINOL (TiHBOL) complex is a very effective catalyst for the reaction, leading to products with very high enantioselectivity (up to 99% ee) and yield (92%). The hetero-Diels-Alder reaction of other aldehydes with 1 under the catalysis of TiHBOL is a general reaction which proceeds well with very high enantioselectivity and isolated yield for various aldehydes at 0 degrees C to room temperature. Based on the experimental results, the proposed mechanism of the hetero-Diels-Alder reaction and the dihedral angle effects of ligands are discussed.     

Friedel-crafts cyclisations. II. Further studies of polyphosphoric acid-catalysed cyclisations of N-cinnamoyl derivatives of aromatic amines

Further studies of the effects of substituents in the N-phenyl nucleus on the polyphosphoric acid-catalysed cyclisation of cinnamanilide to 4-phenyl-3,4-dihydrocarbostyril have confirmed that the isomerisation is prevented by a nitro group and retarded by other substituents in the ortho position to the NH- group. Although a methyl group ortho to the only position at which cyclisation can occur was also shown to retard the reaction, N-cinnamoyl-2,4,5-trichloroaniline was cyclised in moderate yield after prolonged heating, but the 2,4-dibromo and 2,5-dimethoxy analogues were not isomerised. Isomerisation of 2-cinnamamidobiphenyl to 4,8-diphenyl-3,4-dihydrocarbostyril was accompanied by cyclodehydration to 6-styrylphenanthridine. Five new derivatives of cinnamanilide and eight new derivatives of 4-phenyl-3,4-dihydrocarbostyril are described.     

Reactivity of 1,2-cyclic sulfite xylosides towards nucleophiles

1,2-Cyclic sulfite xylosides offer facile access to 1,2-oxazolines upon reaction with aromatic and alkyl nitriles under Lewis or Brönsted acid conditions. Additionally, hydrophobic ionic liquids facilitate acid-catalysed formations of such oxazolines and C- and O-linked xylosides, providing means to carry out fast reactions at room temperature, and this in yields comparable to reactions conducted in xylene at high temperature for extended reaction time.     

Silylium ion-catalyzed challenging Diels-Alder reactions: the danger of hidden proton catalysis with strong Lewis acids

The pronounced Lewis acidity of tricoordinate silicon cations brings about unusual reactivity in Lewis acid catalysis. The downside of catalysis with strong Lewis acids is, though, that these do have the potential to mediate the formation of protons by various mechanisms, and the thus released Br?nsted acid might even outcompete the Lewis acid as the true catalyst. That is an often ignored point. One way of eliminating a hidden proton-catalyzed pathway is to add a proton scavenger. The low-temperature Diels-Alder reactions catalyzed by our ferrocene-stabilized silicon cation are such a case where the possibility of proton catalysis must be meticulously examined. Addition of the common hindered base 2,6-di-tert-butylpyridine resulted, however, in slow decomposition along with formation of the corresponding pyridinium ion. Quantitative deprotonation of the silicon cation was observed with more basic (Mes)(3)P to yield the phosphonium ion. A deuterium-labeling experiment verified that the proton is abstracted from the ferrocene backbone. A reasonable mechanism of the proton formation is proposed on the basis of quantum-chemical calculations. This is, admittedly, a particular case but suggests that the use of proton scavengers must be carefully scrutinized, as proton formation might be provoked rather than prevented. Proton-catalyzed Diels-Alder reactions are not well-documented in the literature, and a representative survey employing TfOH is included here. The outcome of these catalyses is compared with our silylium ion-catalyzed Diels-Alder reactions, thereby clearly corroborating that hidden Br?nsted acid catalysis is not operating with our Lewis acid. Several simple-looking but challenging Diels-Alder reactions with exceptionally rare dienophile/enophile combinations are reported. Another indication is obtained from the chemoselectivity of the catalyses. The silylium ion-catalyzed Diels-Alder reaction is general with regard to the oxidation level of the α,β-unsaturated dienophile (carbonyl and carboxyl), whereas proton catalysis is limited to carbonyl compounds.     

Auto-tandem catalysis in the synthesis of substituted quinolines from aldimines and electron-rich olefins: cascade Povarov-hydrogen-transfer reaction

We demonstrated a catalytic cascade inverse electron demand hetero-Diels-Alder reaction (Povarov reaction) and hydrogen-transfer process. The reaction of electron-rich olefins and excess amount of imines in the presence of acid catalysts under appropriate conditions affords substituted quinolines in a single operation. In the cascade process, the catalysts, such as Tf2NH, TfOH, and Lewis acids, catalyze two mechanistically distinct reactions (auto-tandem catalysis). We also describe the synthetic utility of the prepared quinolines.     

diastereoselective intramolecular Alder-Ene reaction on chiral perhydro-1,3-benzoxazines. a rapid entry to enantiopure cis-3,4-disubstituted pyrrolidines

Chiral 3-acryloyl-2-vinyl-substituted 1,3-perhydrobenzoxazines derived from (-)-8-aminomenthol participate in an ene reaction leading to 3,4-disubstituted pyrrolidinone derivates with excellent diastereoselectivity. The cycloadducts were transformed into enantiopure 3,4-disubstituted pyrrolidines after elimination of the chiral adjuvant.     

Stereoselective synthesis of 2,4,5-trisubstituted piperidines by carbonyl ene and Prins cyclisations

An approach to 2,4,5-trisubstituted piperidines is reported, in which the key step is the Prins or carbonyl ene cyclisation of aldehydes of the type 1. Prins cyclisation catalysed by concentrated hydrochloric acid in CH(2)Cl(2) at -78 degrees C afforded good yields of two of the four possible diastereomeric piperidines, with the 4,5-cis product 7 predominating in a diastereomeric ratio of up to 94:6. The diastereoselectivity of the cyclisation decreased as the 2-substituent increased in size, becoming unselective for very bulky 2-substituents. In contrast, cyclisation catalysed by MeAlCl(2) in CH(2)Cl(2) or CHCl(3) at temperatures of between 20-60 degrees C, favoured the 4,5-trans diastereomer 8, in a diastereomeric ratio of up to 99:1. The low-temperature cyclisations catalysed by HCl proceed under kinetic control via a mechanism involving the development of significant carbocationic character, in which the 4,5-cis cation is more stable than the 4,5-trans cation as a result of overlap with the neighbouring oxygen. The cyclisations catalysed by MeAlCl(2) proceed under thermodynamic control, affording the product in which both the 4- and 5-substituents are equatorial.     

Conjugate addition of organocuprates to chiral bicyclic delta-lactams. Enantioselective synthesis of cis-3,4-disubstituted and 3,4,5-trisubstituted piperidines

[reaction: see text] Chiral nonracemic bicyclic lactam 3, easily accessible by cyclodehydration of (R)-phenylglycinol and racemic methyl 4-formylhexanoate, was converted to the unsaturated lactams 5, which undergo the stereoselective conjugate addition of lower order cyanocuprates to ultimately lead to enantiopure cis-3,4-disubstituted and 3,4,5-trisubstituted piperidines.     

Steric and conformational control of the regioselectivities in the ene reaction with trisubstituted cycloalkenes: comparison of the enophiles singlet oxygen, triazolinedione, and nitrosoarene

The nitrosoarene ene reaction with the cycloalkenes 1-3 and E-4 proceeds in high twix regioselectivity to afford the hydroxylamine ene products 1a-4a (twix) and 1b-4b (twin, except far E-4 twix). Steric interactions in the enophile attack are responsible for the skew trajectory of the nitrosoarene enophile. For Z-1-methylcyclooctene (Z-4), twin abstraction dominates, caused by conformational constraints (transannular interactions) in the hydrgogen-atom abstraction. The balance between these steric and conformational factors dictates the regioselectivity in the ene reaction     

Solid-phase synthesis of aspartic peptidase inhibitors: 3-alkoxy-4-aryl piperidines

[reaction: see text]. The 3-alkoxy-4-aryl piperidines are non-peptide peptidomimetic inhibitors of several aspartic peptidases. The solid-phase functionalization of 3,4-disubstituted piperidine scaffolds using a traceless linker strategy is described. Synthesis of diverse analogues based on this scaffold provides the potential to generate selective inhibitors of this important class of peptidase.