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.     

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

Cyclisation of aldehydes 3-e catalysed by concentrated hydrochloric acid affords predominantly the all cis 2,4,5-trisubstituted piperidines 4a-ewhen the 2-substituent is small, while catalysis by MeAlCl2 in refluxing chloroform gives the trans piperidines 5a-e with diastereomeric ratios of up to 99:1.     

Stereoselective synthesis of 3,4-disubstituted and 3,4,5-trisubstituted piperidines by Lewis acid-catalysed ene cyclisation of 4-aza-1,7-dienes

The thermal or Lewis acid-catalysed ene cyclisation of a variety of 4-aza-1,7-dienes afforded 3,4-disubstituted or 3,4,5-trisubstituted piperidines. Activation of the enophile with a single ester facilitated a thermal ene cyclisation, although the reaction was not amenable to Lewis acid catalysis. With other activating groups on the enophile it was found that Lewis acid catalysis was facile, although there was a fine balance between the desired ene cyclisation and the competing hetero-Diels-Alder reaction, with the product distribution being influenced by the activating group on the enophile, the nature of the ene component, and the Lewis acid used. Activation of the enophile with an oxazolidinone function facilitated Lewis acid-catalysed cyclisation to afford mixtures of ene and hetero-Diels-Alder products. Activating the enophile with two ester groups gave a substrate that underwent a very facile ene cyclisation catalysed by MeAlCl(2) to give the corresponding trans 3,4-disubstituted piperidines with diastereomeric ratios of >200 : 1.     

Further studies on silatropic carbonyl ene cyclisations: beta-crotyl(diphenyl)silyloxy aldehyde substrates; synthesis of 2-deoxy-2-C-phenylhexoses

Silatropic carbonyl ene cyclisations of beta-(allylsilyloxy)- and beta-(crotylsilyloxy)butyraldehydes are shown to proceed with high stereoselectivity but at a much reduced rate in comparison to the cyclisation of analogous alpha-substrates. In the second section, olefin cross-metathesis is explored as a route to substituted alpha-(allylsilyloxy)aldehydes and the method applied to the synthesis of diastereomeric 2-deoxy- and 2-deoxy-2-C-phenyl hexose derivatives from butanediacetal-protected D-glyceraldehyde.     

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 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.     

Tris(trimethylsilyl)silane: an unprecedented enhancement in the diastereoselectivity of radical cyclisations to give 2,4-disubstituted piperidines

Cyclisation of bromides 4a-f mediated by tributyltin hydride affords predominantly the trans piperidines 5a-f with modest diastereomeric ratios, while cyclisation with tris(trimethylsilyl)silane affords the same products with diastereomeric ratios of up to 99 : 1.     

A diastereoselective ring contraction of 1,3-dioxepins to 2,3,4-trisubstituted and tetrasubstituted tetrahydrofurans

A modular and diastereoselective approach to 2,3,4-trisubstituted and tetrasubstituted tetrahydrofurans is reported. The use of dioxepins containing an embedded vinyl acetal functionality leads to a Lewis acid-mediated [1,3] ring contraction to afford tetrahydrofurans in good yield and excellent diastereoselectivity. The use of TMSOTf in MeCN leads to the 2,3-cis/3,4-trans diastereomer while SnCl4 in CH2Cl2 provides the 2,3-trans/3,4-cis diastereomer. A variety of substituents are tolerated at each position. The presence of Lewis basic functionality under the SnCl4 conditions alters the reaction favoring the diastereomer formed under the TMSOTf conditions. We present conclusive evidence that the products of each of these reactions are formed under kinetic control. We further provide stereochemical models consistent with each of these rearrangement reactions that account for the formation of the major diastereomer in each case.     

Free radical cyclisation of enamides leading to biologically important γ-lactams

This review describes the free radical cyclisation of enamides using tributyltin hydride, manganese(III) acetate, copper(I) complexes or dichlorotris(triphenylphosphine)ruthenium(II). These cyclisations can proceed via either 4-exo or 5-endo pathways, to produce β- or γ-lactam products, respectively. In general, the reactions produce γ-lactams derived from an unusual (disfavoured) 5-endo-trig radical cyclisation. These results can be explained on the basis of a reversible cyclisation mechanism; the 4-exo cyclisation produces the kinetically favoured β-lactam while the 5-endo cyclisation produces the thermodynamically more stable γ-lactam.     

Glycosidation-anomerisation reactions of 6,1-anhydroglucopyranuronic acid and anomerisation of beta-D-glucopyranosiduronic acids promoted by SnCl(4)

The reaction of silylated nucleophiles with 6,1-anhydroglucopyranuronic acid (glucuronic acid 6,1-lactones) catalysed by tin(IV) chloride provides 1,2-trans or 1,2-cis (deoxy)glycosides in a manner dependent on the donor structure. The alpha-glycoside was obtained for reactions of the donor with the 2-acyl group and 2-deoxydonors, whereas the 2-deoxy-2-iodo donor gave the beta-glycoside. Experimental evidence shows that when 1,2-cis-glycoside formation occurs, the anomerisation of initially formed 1,2-trans-glycosides catalysed by SnCl(4) is possible. The anomerisation of beta-D-glucopyranosiduronic acids was found to be faster, in some cases, than anomerisation of related beta-D-glucopyranosiduronic acid esters and beta-D-glucopyranoside derivatives and the rates are dependent on the structure of the aglycon. Moreover, the rates of anomerisation of beta-D-glucopyranuronic acid derivatives can be qualitatively correlated with rates of hydrolysis of beta-D-glucopyranosiduronic acids. Mechanistic possibilities for the reactions are considered.     

Factors controlling the alkyne prins cyclization: the stability of dihydropyranyl cations

The relative stability of the intermediates involved in the alkyne Prins cyclization and the competitive 2-oxonia-[3,3]-sigmatropic rearrangement was studied. This rearrangement was shown to occur slowly under typical alkyne Prins cyclization conditions when the allenyl oxocarbenium ion that results from the rearrangement is similar to or higher in energy than the starting alkynyl oxocarbenium ion. The formal 2-oxonia-[3,3]-sigmatropic rearrangement may be disfavored by destabilizing the resultant allenyl oxocarbenium ion or by stabilizing an intermediate dihydropyranyl cation. The trimethylsilyl group as a substituent at the alkyne and electron-withdrawing groups (CH2Cl and CH2CN) located at the alpha-position to the carbinol center are shown to be effective. DFT calculations suggest that these substituents stabilize the dihydropyranyl cations, thus leading to a more uniform reorganization of the electronic density in the ring, and do not have a direct effect on the formally positively charged carbon atom.     

One-pot direct conversion of 2,3-epoxy alcohols into enantiomerically pure 4-hydroxy-4,5-dihydroisoxazole 2-oxides

[structure: see text]. A new methodology for the one-pot direct conversion of 2,3-epoxy alcohols into enantiomerically pure 4-hydroxy-4,5-dihydroisoxazole 2-oxides 1 has been found. The reaction works at room temperature and can be run at the 5-10 g scale. The mixture of 4,5-cis and 4,5-trans isomers obtained can be separated as such or as the bis-TDS ethers. A preliminary example of reductive cleavage of 1 to the corresponding amino polyol is also reported.     

Synthese radicalaire d'analgesiques potentiels: aryl-4 piperidines substituees en 2 et benzomorphanes

The synthesis of a series of 3-aryl 5-hexenyl amines and the cyclisations of the corresponding N-chloroamines are described. When the ring closure results from the amino radical addition to the ethylenic double bond, 2-chloromethyl 4-phenyl piperidines are obtained. These compounds lead by intramolecular Friedel-Craft reaction to varied substituted 6,7-benzomorphanes. When the phenyl ring is substituted with a methoxyl group, the cyclisation proceeds via homolytic aromatic substitution and 4-allyl tetrahydroquinolines are formed.     

Methanol addition to dihapto-coordinated rhenium complexes of furan

The complexes [TpRe(CO)(L)(4,5-eta(2)-furan)], present as diastereomeric mixtures (L = (t)BuNC (1A, 1B), PMe(3) (2A, 2B), pyridine (3A, 3B), or 1-methylimidazole (4A, 4B)), undergo acid-catalyzed methanol addition in CH(2)Cl(2) at -40 degrees C, resulting in the syntheses of dihapto-coordinated 2-methoxy-2,3-dihydrofuran complexes. In all cases, two diastereomers resulted, one in which the oxygen of the dihydrofuran is oriented toward the L ligand (5A, 6A, 7A, and 8A), and one in which the oxygen is oriented away from the L ligand (5B, 6B, 7B, and 8B). In all cases, the methoxy group adds stereoselectively, anti to the metal fragment. In addition, the (t)BuNC complex 1 yields a dihapto-coordinated vinyl ether (5C) that results from ring opening of the protonated furan ligand. In no case does the diastereomeric ratio of products correlate with that of the starting material.     

Aromatic 4-tetrahydropyranyl and 4-quinuclidinyl cations. Linking Prins with Cope and Grob

The chair 4-tetrahydropyranyl cation and the 4-quinuclidinyl cation are shown to be energy minima and to be delocalized, with exceptionally long CH2CH2 bonds, according to B3LYP/6-31G* calculations; the implications for Prins cyclizations, Cope rearrangements, and Grob fragmentations are discussed.     

General strategy for stereoselective synthesis of 1-substituted exo,endo-2,6-diaryl-3,7-dioxabicyclo[3.3.0]octanes: total synthesis of (+/-)-gmelinol

[reaction: see text] A general strategy for stereoselective synthesis of 1-substituted exo,endo-2,6-diaryl-3,7-dioxabicyclo[3.3.0]octanes including (+/-)-gmelinol from (2,3-trans)-(4,5-cis)-alpha-aroylparaconic esters, which are readily obtained from the reaction of vicinal dianions derived from alpha-aroylsuccinic esters with aromatic aldehydes, is described. The synthetic sequence involves alpha-methylation or alpha-hydroxylation, reduction, bislactonization, and reduction followed by furofuran formation.     

An MO study of regioselective amine addition to ortho-quinones relevant to melanogenesis

Energy profiles for alternative intramolecular cyclisations of 4-(aminoalkyl)-ortho-quinones have been calculated using the AM1 method and ab initio energies of the transition states are determined. In all the cases cyclisation at position 5 occurs via a significantly lower energy transition state than cyclisation at position 3. This is consistent with experimental observations. Optimal trajectories for attack have been determined from a study of the reactions of methylamine with 4-methyl-ortho-quinone. For cyclisation of aminoalkyl derivatives deviation from the optimal direction is less for reaction at position 5 but constraint on angle of attack only partially accounts for the regioselectivity. Intrinsic differences in the electronic energies of the alternative transition states are the main contributor to regioselectivity. The relative energies of transition states can be modified by variation of the substituent at position 4. The calculations suggest that seven-membered ring formation may occur via a boat transition state and steric hindrance in the seven-membered transition states may account for the experimentally observed influence of N-substituents on the mode of reaction.     

Some new aspects of benzyne and radical mediated cyclisations

KNH₂/NH₃ cyclisations of some alkoxy substituted arylhalides proceed in poor yields. This shortcoming may be overcome by the use of LDA/THF to effect the ring closure which may occur through benzyne or radical intermediates. Besides ortho halogenated dihydroanils and amides, the cyclisation of the benzylamine Schiff bases also provides a convenient route to isoquinoline alkaloids.     

Direct observation of a 14-electron ruthenacyclobutane relevant to olefin metathesis

The 14-electron ruthenium phosphonium alkylidene complex [(IH2Mes)Cl2Ru=CH(PCy3)][B(C6F5)4], 1b, a highly active olefin metathesis catalyst, reacts with stoichiometric quantities of ethylene at -50 degrees C in CD2Cl2 to generate the ruthenacyclobutane complex [(IH2Mes)Cl2RuCH2CH2CH2], 2, and [CH2=CH(PCy3)][B(C6F5)4] in quantitative yield by NMR spectroscopy. 1H and 13C NMR spectroscopies on 2 and 2-13C3 are consistent with a symmetrical C2v structure, providing the first experimental information concerning this crucial intermediate in ruthenium-mediated olefin metathesis. At -50 degrees C, exchange with free ethylene takes place on the chemical time scale. Complex 2 decomposes in solution upon warming to room temperature, generating propene and unknown ruthenium product(s).     

Organometallic enantiomeric scaffolding: a strategy for the enantiocontrolled construction of regio- and stereodivergent trisubstituted piperidines from a common precursor

Reported herein is a general and efficient method to construct 2,3,6-trisubstituted piperidines in a substituent-independent fashion. From the high enantiopurity organometallic scaffold (-)-Tp(CO)(2)[(η-2,3,4)-(1S,2S)-1-benzyloxycarbonyl-5-oxo-5,6-dihydro-2H-pyridin-2-yl)molybdenum (Tp = hydridotrispyrazolylborato), a variety of TpMo(CO)(2)-based 2,3,6-trifunctionalized complexes of the (η-3,4,5-dihydropyridinyl) ligand were easily obtained in 5 steps through a sequence of highly regio- and stereospecific metal-influenced transformations (15 examples). From the 2,3,6-trifunctionalized molybdenum complexes, either 2,6-cis-3-trans or 2,3,6-cis systems were selectively obtained through the choice of an appropriate stereodivergent demetalation protocol. The potential of this strategy in synthetic chemistry was demonstrated by the short total synthesis of four natural and one non-natural alkaloids: indolizidines (±)-209I and (±)-8-epi-219F in the racemic series, and enantiocontrolled syntheses of (-)-indolizidine 251N, (-)-quinolizidine 251AA, and (-)-dehydroindolizidine 233E.