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Novel heterogeneous catalysts were prepared by impregnation of titania with a solution of cobalt acetate/melamine and subsequent pyrolysis. The resulting materials show an unusual nitrogen-modified titanium structure through partial implementation of nitrogen into the support. The optimal catalyst displayed good activity and selectivity for challenging pyridine hydrogenation under acid free conditions in water as solvent.

An acid-mediated 6-endo-trig cyclisation of amine-substituted enones has been developed for the stereoselective synthesis of trans-6-alkyl-2-methyl-4-oxopiperidines. Performed under conditions that prevent removal of the Boc-protecting group or acetal formation, the key cyclisation was found to generate cleanly the 4-oxopiperidine products in high overall yields from a wide range of alkyl substituted enones. The synthetic utility of the trans-6-alkyl-2-methyl-4-oxopiperidines formed from this process was demonstrated with the total synthesis of the quinolizidine alkaloid, (+)-myrtine and the piperidine alkaloid, (-)-solenopsin A.

Scope and limitations in the diastereoselective preparation of 2,6-cis or 2,6-trans disubstituted piperidines are described, through intramolecular reaction of chiral β′-carbamate-α,β-unsaturated ketone. This methodology has been applied to the total synthesis of a few well chosen examples, such as (-)-solenopsine A and alkaloid (+)-241D.

The synthesis of chiral 2-cyano-Δ4-tetrahydropyridine 5 was carried out in 85 % yield through a modified two-step Fry reductive cyanation of pyridinium salt (+)-3c that used lithium triethylborohydride as the hydride donor. An alkylation-reduction sequence provided 2-alkyl-substituted tetrahydropyridines (+)-10a and (+)-10b in 72-75 % yield after chromatographic purification. This protocol has been applied to the asymmetric syntheses of piperidine alkaloids (-)-coniine and (-)-solenopsin A. The two-step reductive cyanation of chiral pyridinium salt (+)-3c afforded α-amino nitrile 5 in 85 % yield, which underwent an alkylation-reduction sequence followed by removal of the chiral moiety to yield the hemlock alkaloid (-)-coniine as its mandelate salt (>99:1 er). This reaction sequence was also used for the synthesis of the trans-2,6-disubstituted piperidine alkaloid (-)-solenopsin A. Copyright

A metal-free direct hydrogenation of pyridines was successfully realized by using homogeneous borane catalysts generated from alkenes and HB(C 6F5)2 via in situ hydroboration. The reaction affords a broad range of piperidines in high yields with excellent cis stereoselectivities.

Two strategies, "hydrogenation-hydride reduction" and "quaternization-hydride reduction", are reported that make use of mild reaction conditions (room temperature) to efficiently remove the N-pyridin-2-yl directing group from a diverse set of C-2-substituted piperidines that were synthesized through directed Ru-catalyzed sp3 C-H functionalization. The deprotected products are obtained in moderate to good overall yields irrespective of the strategy followed, indicating that both methods are generally equally effective. Only in the case of 2,6-disubstituted piperidines, could the "quaternization-hydride reduction" strategy not be used. The "hydrogenation-hydride reduction" protocol was successfully applied to trans- and cis-2-methyl-N-(pyridin-2-yl)-6-undecylpiperidine in a short synthetic route toward (±)-solenopsin A (trans diastereoisomer) and (±)-isosolenopsin A (cis diastereoisomer). The absolute configuration of the enantiomers of these fire ant alkaloids could be determined via VCD spectroscopy.

The efficient total synthesis of ( ± ) solenopsin A ( 9 ) was achieved in a series of eight steps starting from readily available N -Bn-N -Boc alanine derivative 1. Copyright by Walter de Gruyter.

A protocol for rapid access to the relative and absolute configurations of the solenopsins, the venom alkaloids of fire ants (Solenopsis spp.), was developed based on chiral capillary gas chromatography. The synthesis of racemic mixtures of 2-methyl-6-alkylpiperidines and the isolation of natural (2R,6R)- and (2R,6S)-2-methyl-6-undecylpiperidines allowed for the standardization of the chromatographic method. Application of this protocol revealed the previously unknown natural occurrence of four stereoisomers of 2-methyl-6-undecylpiperidine in venom samples from workers and gynes of Solenopsis saevissima.

A general directed Ru-catalyzed C(sp3)-H α-alkylation protocol for piperidines (less-reactive substrates than the corresponding five-membered cyclic amines) has been developed. The use of a hindered alcohol (2,4-dimethyl-3-pentanol) as the solvent and catalyst activator, and a catalytic amount of trans-1,2-cyclohexanedicarboxylic acid is necessary to achieve a high conversion to product. This protocol was used to effectively synthesize a number of 2-hexyl- and 2,6-dihexyl piperidines, as well as the alkaloid (±)-solenopsin A. Kinetic studies have revealed that the carboxylic acid additive has a significant effect on catalyst initiation, catalyst longevity, and reverses the reaction selectivity compared with the acid-free reaction (promotes alkylation versus competing alkene reduction). Acid makes the difference! A directed Ru-catalyzed C(sp3)-H α-alkylation protocol for cyclic amines has been developed (see scheme). Kinetic studies revealed that the carboxylic acid aids catalyst activation, increases catalyst longevity, and reverses the reaction selectivity. The alcohol selected as the solvent plays an active role in the catalysis. Copyright

(Chemical Equation Presented) Concise and efficient methods for the synthesis of enantiomers of fire ant venom alkaloids solenopsin and isosolenopsin A, B, and C are described. These syntheses are based on diastereoselective electrophilic substitution of enatiomerically-pure α-lithiated 2-alkylpiperidine.

A novel C2-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester 1 was prepared by the double asymmetric allylboration of glutaldehyde followed by an aminocyclization and carbamation. On the basis of desymmetrization of 1 using iodocarbamation, one allyl group of 1 was protected and monofunctionalizations of the resulting oxazolidinone 11 were performed. The reaction of the N-methoxycarbonyl piperidine 25 employing decarbamation reagent (n-PrSLi or TMSI) as a key step gave oxazolidinone 26 or 17 including an intramolecular ring formation, which was transformed in a few steps into (-)-porantheridine (2) and (-)-2-epi-porantheridine (3), respectively. In addition, the expedient synthesis of (+)-epi-dihydropinidine (4), (2R,6R)-trans-solenopsin A (5), and precoccinelline (6), starting from 11 is described. The Royal Society of Chemistry 2006.

The fire ant venom alkaloid (±)-solenopsin A was prepared in 4 steps (34%) starting from the N-phenyl-2-undecyl piperidine (1c). The key step in this synthesis involved the dearomatization of the phenyl group of N-phenyl-2-methyl-6-undecyl-piperidine (9c), which was carried out under Birch conditions.

(Chemical Equation Presented) Hg(II)-mediated tandem Overman rearrangement and intramolecular amidomercuration reactions were proven to provide a convenient tool for the stereoselective synthesis of cis- and frans-2,6-disubstituted piperidines. Thus, upon treatment with Hg(OTFA) 2 in THF, the trichloroacetimidate 1 directly transformed into the 2,6-dialkyl piperidine 2 with almost exclusive trans selectivity. The amiodomercuration reaction of the carbamate 7 by Hg(OTFA)2 in nitromethane showed an excellent cis selectivity. Also reported is the stereoselective synthesis of solenopsin A and isosolenopsin A.

Starting from a common lactam, (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (1), or its enantiomer, the enantioselective synthesis of 2-alkylpiperidines and cis- and trans-2,6-dialkylpiperidines is reported. The potential of this approach is illustrated by the synthesis of the piperidine alkaloids (R)-coniine, (2R,6S)-dihydropinidine, (2R,6R)-lupetidine, and (2R,6R)-solenopsin A, the indolizidine alkaloids (5R,8aR)-indolizidine 167B and (3R,5S,8aS)-monomorine I, and the nonnatural base (4R,9aS)-4-methylquinolizidine.

C(2)-symmetric 2,6-diallylpiperidine 1-carboxylic acid methyl ester (5) was examined via the double asymmetric allylboration of glutaraldehyde followed by aminocyclization and carbamation as a promising chiral building block for piperidine-related alkaloids, which were synthesized by the desymmetrization of 5 using intramolecular iodocarbamation as a key step. [reaction: see text]

The enantioselective syntheses of (S)-coniine and (2R,6R)-trans-solenopsin A are reported. The key step in both syntheses is the catalytic asymmetric hydrosilylation of a cyclic imine.

The enantioselective synthesis of the trans-2,6-dialkylpiperidine alkaloids (2R,6R)-lupetidine and (2R,6R)-solenopsin A from 6-methyl-2- piperidone 1 is described. The key step of this synthesis consists of the addition of a dialkylcopper derivative to the thioimidate salt 3 followed by sodium borohydride reduction of the resulting iminium salt.

Solenopsins A, B and C have been synthesized in enantiomerically pure forms from the corresponding anti-1,5-diols which have been obtained from glutaric anhydride by an asymmetric synthesis induced by chiral sulfoxides.

The trans-piperidine alkaloid, (-)-solenopsin A, was prepared in seven steps from readily available 4-methoxy-3-(triisopropylsilyl)pyridine in 43% overall yield.

Heating cyclic 2-carbonylsultam-substituted N-hydroxylamines 4 with NaH yields sultam auxiliary 8 and imines 10, which are trapped in situ either by i-Bu2AlH or organocerium reagents to give enantiomerically pure 2-mono- or trans-2,6(2,5)-disubstituted piperidines (pyrrolidines) 11 or 12.

Sequences of α'-lithiations and electrophilic substitutions of Boc-pyrrolidines, Boc-piperidines, and Boc-hexahydroazepines that provide compounds which are substituted adjacent to nitrigen are reported, and the pathways of the reactions are discussed.By this methodology monosubstituted 2 and disubstituted 2,4, 2,6, and 2,5 Boc-piperidines are obtained as single or separable diastereoisomers consistent with equatorial lithiations and retentive electrophilic substitution in chair conformations.Both cis and trans 2,6-disubstituted diastereoisomers can be prepared, and control of diastereoselectivity is demonstrated by syntheses of solenopsin A, a 2,6-trans-disubstituted piperidine, and of Boc-dihydropinidine, a 2,6-cis-disubstituted piperidine.In the case of 3-methoxy-Boc-piperidine elimination of methoxide occurs upon lithiation, and with cis-2,4-disubstituted Boc-piperidines the electrophile is introduced with trans stereochemistry at C-6.These reactions are suggested to involve twist boat conformations consistent with an X-ray crystal structure of 2-methyl-6-(trimethylstannyl)-4-phenyl-N-Boc-piperidine.Boc-pyrrolidine lithiates more rapidly than Boc-piperidine, provides 2-substituted products with electrophiles, and on further lithiation-substitution gives 2,5-cis- and -trans substituted products.Boc-perhydroazepine provides 2-substituted products by the sequence and on further lithiation-substitution gives 2,7-trans-disubstituted products.

Enantiomerically pure solenopsin A and B (1 and 2) are constituents of the venom of fire ant, Solenopsis invicta (= S. saevissima), the habitat of which is the south-east part of the United States of America (Scheme 1). Both molecules are biologically active in having hemolytic, insecticidal and antibiotic properties. Desite the apparent simplicity of their structure, the synthesis of the enantiomerically pure isomers is not trivial. The essential problem lies in the creation of the trans configuration for the 2,6-dialkyl substituents. So far four solutions have been reported. The first entails the transfer of chirality on successive alkylations of 2-cyano-6-oxazolopiperidine. The second involves the diastereoselective reduction of a bornyl β-keto ester to a chiral secondary alcohol which by conversion to its azide and subsequent internal dipolar addition controls the construction of the 2-methylpiperidine ring. The third depends essentially on the cyclization of 6R-aminoheptadecan-2-one to the related 1,2-dehydropiperidine which is then selectively reduced. The fourth solution exploits the innate chirality of 5-methyl L-glutamate which on elaboration provides an analogous amino-ketone which undergoes stereocontrolled cyclization. We now describe a practical enantiospecific synthesis of 1 that embodies the chief features of the last two approaches, but which takes advantage of our procedure for preparing enantiomerically pure β-amino acids from aspartic acid.

The stereoselective reduction of 1-(tert-butoxycarbonyl)-4-chloro-2,6-dialkyl-1,2-dihydropyridines 6 and 22 was studied.Reduction of 6 with Et3SiH/TFA gave the cis-2,6-dialkyl-1,2,5,6-tetrahydropyridine 7 as the major product.The stereoselectivity was reversed by reducing 6 with NaBH3CN/TFA, which gave predominantly the trans-2,6-dialkyltetrahydropyridine 10.Catalytic hydrogenation of 7 and 10 gave the corresponding N-Boc-cis(or trans)-2,6-dialkylpiperidines.Regioselective hydrogenation of 6 gave the 1,2,3,4-tetrahydropyridine 18, which on treatment with NaBH3CN/TFA provided a 90:10 mixture of trans- and cis-piperidines 15 and 16.More vigorous hydrogenation of 6 afforded the cis-piperidine 15 with 96percent stereoselectivity.Similar stereoselective reductions of dihydropyridine 22 were carried out.Stereoselective reductions of dihydropyridines 6 and 22 were utilized in the synthesis of (+/-)-solenopsin A and (+/-)-dihydropinidine from 4-chloropyridine in six and five steps, respectively.

It was observed that diastereofacial selectivity in the addition reaction of organometallics to the chiral imines derived from (R)-2-methoxy-1-phenylethylamine was regulated under appropriate conditions; i. e., organolithium and organocerium reagents added from the re-face of the chiral imines selectively, while organocopper reagents attacked from the si-face.The utility of the present method was demonstrated in the enantioselective synthesis of solenopsin A.

ω-Alkyllactams 3 can be transformed into ω-alkyl cyclic β-enaminoesters 7 which are good precursors of insects venom alkaloids.A stereoselective synthesis of dialkylpyrrolidines and Solenopsine A is described followed by and easy stereochemical determination by 13C nmr.

Intramolecular amidomercuriation of methyl N-hept-6-en-2-ylcarbamate and reaction of the resulting organomercurial with sodium borohydride in the presence of acrylonitrile or dec-1-en-3-one has been used to prepare trans-2,6-dialkylpiperidines.A more stereoselective route lies in the cycloaddition of alkenes to 2-alkyl-2,3,4,5-tetrahydropyridine oxides followed by reductive cleavage of the resulting perhydroisoxazolopyridine.Both procedures are illustrated by synthesis of the fire ant-venom alkaloid, solenopsin A.

The reduction of 2,5-pyrrolines can be run with a correct selectivity.

A new methodology is described for the coupling of allylsilanes and nitrones with trimethylsilyl triflate as a catalyst to afford homoallylhydroxylamines in yields ranging from 70percent to 95percent.Lower yields were obtained with shorter reaction times.The reaction also proceeds intramolecularly, giving mixtures of cis and trans tetrahydropyridines in excellent yield.The TMSOTf-catalyzed process is compared and contrasted with the thermally induced intramolecular nitrone cycloaddition.

The imine-epoxide rearrangement, followed by hydride reduction has been used to prepare substituted piperidine derivatives with control of stereochemistry.An application to the synthesis of (+-) solenopsin A is reported.

Syntheses in the pine alkaloid family, the fire ant venom series, and continued studies in the Poranthera species are presented.Reaction of 5-lithio-2-pentanone-2,2-dimethylpropylene ketal or the corresponding dialkylcuprate compound with carboxylic acid derivatives gives selectively protected 1,5-dicarbonyl compounds.After reductive amination of the newly formed ketone function, acidic hydrolysis of the cyclic ketal gives 6-alkyl-2-methyl-3,4,5,6-tetrahydropyridines.Stereoselective reduction of the imine function affords cis-2,6-disubstituted piperidines.Examplesof this approach include syntheses of dihydropinidine from Pinus sabiniana and the fire ant venoms cis-2-methyl-6-undecylpiperidine and 2-methyl-6-undecyl-3,4,5,6-tetrahydropyridine from Solenopis geminata and S. xyloni.A preliminary report on an approach to porantherilidine, from Poranthera corymbosa, is described.

Nucleophilic addition of a variety of alkynyl and alkenyl Grignard reagents to 1-methoxycarbonylpyridinium chloride takes place at the α-position in a highly regioselective manner to give 2-substituted 1-methoxycarbonyl-1,2-dihydropyridines exclusively, while, with alkyl Grignard reagents, a lack of the regioselectivity is observed.These results may be explained by the HSAB principle.The high α-regioselectivity is preserved in the cases of 2-substituted pyridines as well, giving 2,6-disubstituted 1,2-dihydropyridines exclusively, which can be transformed stereoselectively into cis- and trans-2,6-dialkylated piperidines.These highly regioselective α-alkynylations of 1-methoxycarbonylpyridinium salts are exploited in synthesis of 1-azabicycloalkanes as well as (+/-)-solenopsin A.

Use of a novel bicyclic ketal fragmentation protocol provides a simple entry into the sex pheromone of the tussock moth, as well as into the fire ant venom constituent, Solenopsin A.

Saturated heterocycles, as their tert-butylformamidines, may be transformed into enamidines, by metalation-selenation-elimination.These enamidines are valuable precursors to 2-substituted, 2,4-disubstituted, and 2,4,6-trisubstituted pyrrolidines, piperidines, and perhydroazepines, prepared in a regiospecific manner.The method is demonstrated by the synthsesis of selenopsin A and the red fire ant venom.The use of acyclic enamidines is displayed as a homologation reagent which converts carbonyl compounds to higher alkyl derivatives.

Intramolecular amidomercuration of N-methoxycarbonyl-6-aminohept-1-ene and reaction of the resulting organomercurial with sodium borohydride in the presence of acrylonitrile or decen-3-one has been used to prepare trans-2,6-dialkylpiperidines, including solenopsin A, a constituent of the venom of the fire-ant.

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Reactions of N-methoxycarbonyl-2-alkylpyridinium salts with alkynyl Grignard reagents give exclusively 2,6-disubstituted 1,2-dihydropyridines, from which cis- and trans-2,6-dialkylated piperidines can be derived selectively.Consequently, (+)-solenopsine A is efficiently synthesized by this sequence.

The Beckmann rearrangement of oxime sulfonates with simultaneous nucleophilic trapping of the intermediary iminocarbocation by organoaluminum reagents is described.This process provides a new and highly efficient route to imino thioethers, imino selenoethers, imino nitriles, and α-alkylated amines starting from oxime sulfonates by the use of dialkylaluminum thiolates, selenolates, diethylaluminum chloride-trimethylsilyl cyanide, and trialkylaluminum-diisobutylaluminum hydride systems, respectively.The present organoaluminum-promoted Beckmann rearrangement of oxime sulfonates has been successfully applied to the synthesis of naturally occuring alkaloids, pumiliotoxin C and solenopsin A and B, in stereoselective fashion.Moreover, α,α-dialkylation of amines can be realized by the successive treatment of oxime sulfonates with trialkylaluminum followed by allylic or propargylic Grignard reagents in synthetically useful yields.

The cis 2,6-dialkylpiperidine alkaloid (+/-) dihydro-pinidine 7b and the trans alkaloid (+/-) solenopsin A 5a were synthesized from a common α-aminonitrile synthon 1.The key step in this synthesis was the stereoselective reductive decyanation of the 1-benzyl-2-cyano-2',6-dialkylpiperidines 3a and 3b.

Effective and convenient syntheses of solenopsin A and B have been developed which involve the Beckmann rearrangement-alkylation reaction promoted by organoaluminum reagents and a new stereoselective reduction of imino functional group.

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