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The syntheses of seven novel amido nicotine derivatives 12-18 from (S)-nicotine are presented. (S)-Nicotine and (S)-6-chloronicotine derivatives were cross-coupled with the corresponding amides 6-10 at the C-4 position of the pyridine ring via copper(I)-mediated reactions. Derivatives 16-18 were also obtained via copper(II)-mediated reactions from (S)-nicotine containing a C-4 boronic acid pinacol ester group. The optimization of reaction conditions for both routes provided a useful method for preparing C-4 amide-containing nicotine analogs.

A dihydropyridone-mediated approach to the morphine skeleton was investigated. The hexahydroisoquinoline 2 was synthesized in nine steps using N-acylpyridinium chemistry and dihydropyridone functionalization methods. This new approach should be useful in the design of more efficient syntheses of morphine and its derivatives.

The role of twist-boat conformers of cyclohexanones in hydride reductions was explored. The hydride reductions of a cis-2,6-disubstituted N-acylpiperidone, an N-acyltropinone, and tert-butylcyclohexanone by lithium aluminum hydride and by a bulky borohydride reagent were investigated computationally and compared to experiment. Our results indicate that in certain cases, factors such as substrate conformation, nucleophile bulkiness, and remote steric features can affect stereoselectivity in ways that are difficult to predict by the general Felkin-Anh model. In particular, we have calculated that a twist-boat conformation is relevant to the reactivity and facial selectivity of hydride reduction of cis-2,6-disubstituted N-acylpiperidones with a small hydride reagent (LiAlH4) but not with a bulky hydride (lithium triisopropylborohydride).

Concise and highly stereocontrolled total syntheses of racemic and enantiopure frog alkaloid 205B (1) were accomplished in 11 steps from 4-methoxypyridines 6 and 7 in overall yields of 8 and 8%, respectively. The assembly of the core of the natural product relies on a stereoselective Tsuji-Trost allylic amination reaction and a ring-closing metathesis. The synthesis features the use of an N-acylpyridinium salt reaction to introduce the first stereocenter and an unprecedented trifluoroacetic anhydride-mediated addition of an allylstannane to a vinylogous amide with complete facial selectivity. Deoxygenation of the C4 ketone proved difficult but was accomplished via a modified Barton-McCombie reaction in the presence of a catalytic amount of diphenyl diselenide.

A strategy for the synthesis of the lycopodium alkaloid dihydrolycolucine (1) has been investigated. Synthetic routes were developed based on N-acylpyridinium salt chemistry to prepare target fragments 3 and 4 that could ultimately converge to the natural product. Key reactions include IMDA cycloadditions and retro-Mannich ring-openings to form both the AB and the EF ring fragments. The ring C precursor was prepared using pyridine substitution and directed lithiation chemistry. A Suzuki cross-coupling of rings C and EF led to the CEF ring fragment. Initial attempts at closure of the seven-membered D ring were unsuccessful.

A racemic and asymmetric synthesis of cermizine D (1) was accomplished in six steps from 4-methoxypyridine or 4-methoxy-3-TIPS-pyridine in 12% and 13% overall yield, respectively. A key step is a stereoselective 1,4-addition of a 2-((trimethylsilyl)methyl)pyridine-derived cuprate to a bicyclic 2,3-dihydro-4-pyridone. Racemic and (−)-cermizine D failed to exhibit cytotoxicity against four different cell lines.

Herein is described an original approach to access a tricyclic framework of the lepadiformine-type alkaloids. A Grignard/N-acylpyridinium salt reaction of a 4-methoxytetrahydroquinoline is the key carbon–carbon bond-forming step that was used to establish the desired absolute stereochemistry at the C2 position of the target alkaloid. The synthesis features an allylation reaction with an N-acyliminium ion to set the C10 quaternary stereocenter, a mild dissolving-metal cleavage of hindered phenyl carbamates, and an aminoiodocyclization to form the pyrrolidine ring. While this route does not provide the correct C10 stereochemistry, it showcases an efficient method to build analogues with the ring system of this class of alkaloids in 11 steps overall.

ABC and EF ring fragments of spirolucidine have been prepared via asymmetric synthesis using chiral N-acylpyridinium salt chemistry. Model studies have been carried out to support further progress toward the completion of this complex alkaloid.

During the course of a study aimed at constructing azaspirocycles from 2,3-dihydro-4-pyridones, an unexpected product was obtained in the SET ring-opening reaction of photocycloadduct 1. Differences in reactivity between homologues 1 and 2 were observed in the presence of SmI(2). Tricyclic ketone 2 afforded azaspiro[5.5]undecane 15 when treated with SmI(2); however, when ketone 1 was submitted to similar reaction conditions a double ring-opening/reduction sequence gave cis-piperidinol 10.

Hydrophobic tagging of biomolecules has been reported by our group and others to increase their ionization efficiency during electrospray ionization and facilitate their detection by mass spectrometry. As such, hydrophobic tagging should provide a viable method for augmenting MS-based quantification of low abundance proteins by decreasing their detection limits. Herein we have evaluated two commercial alkylation reagents and several newly synthesized hydrophobic alkylation reagents for their utility in quantifying B-type Natriuretic Peptide, a low abundance cardiac biomarker, by protein cleavage isotope dilution mass spectrometry. For the cysteine containing tryptic peptide evaluated, a approximately 3.5-fold decrease in the detection limit was observed for the best performing hydrophobic reagent, 2-iodo-N-octylacetamide, relative to the commonly used alkylation reagent, iodoacetamide. Additionally, we have evaluated the use of nonpolar surface areas as a metric for assessing the effectiveness of the alkylation reagents in improving ESI response.

PC-IDMS experiments for two peptides, laminin nonapeptide and the N-terminal tryptic peptide of prostate specific antigen, were performed utilizing a variety of alkylating reagents. These experiments were conducted to investigate how hydrophobicity influences the limits-of-detection (LOD) by altering their electrospray ionization response. Nonpolar surface areas were calculated for both peptides and all alkylating reagents to provide an estimate of the hydrophobicity of the differently alkylated peptides. Decreases in LOD by 2-fold were observed for both peptides between the best and worst performing combination of alkylating reagent. However, while an increase in hydrophobicity was found to aid in decreasing LOD to an extent, beyond a certain hydrophobicity, we observed a decrease.

Enantiopure (S)-6-alkoxynicotine derivatives have been synthesized in two steps from (S)-nicotine via (S)-6-iodonicotine. Deprotonation and substitution at the C-5 position of the pyridine ring of (S)-6-methoxynicotine were achieved using mesityllithium as the base at 0 °C. Conditions for the C-4 lithiation/substitution of (S)-6-isopropoxynicotine and (S)-5-chloro-6-methoxynicotine were also developed.

The wide range of protein concentrations found in biological matrixes presents a formidable analytical challenge in proteomics experiments. It is predicted that low-abundance proteins are the likely clinically relevant targets in disease-based proteomics analyses. To effectively analyze low-abundance proteins by electrospray ionization mass spectrometry, limits of detection must be improved upon. Previous studies have demonstrated hydrophobicity is a main determinant of the electrospray ionization response. One would expect to improve the electrospray ionization response of a hydrophilic peptide by making it more hydrophobic, thus increasing the molecule's affinity for the surface of the electrospray droplet, thereby allowing the molecule to more effectively compete for charge. In this report, we demonstrate a strategy to increase the electrospray ionization response of cysteine-containing peptides with the addition of an octylcarboxyamidomethyl modification via alkylation chemistry, which we name the ALiPHAT strategy (augmented limits of detection for peptides with hydrophobic alkyl tags). We demonstrate the relative increase in electrospray ionization response of peptides with an octylcarboxyamidomethyl modification compared to carboxyamidomethyl-modified peptides upon LC-MS analysis. Furthermore, we show the octylcarboxyamidomethyl group does not fragment or undergo neutral loss during collision-induced dissociation. Collectively, our results demonstrate the feasibility of the octylcarboxyamidomethyl modification to improve limits of detection for cysteine-containing peptides.

Novel acylpyridinium salt chemistry and directed lithiation methodology was developed to add for the first time substitutions directly to the phenylpyridine heterocyclic ring of nicotine. A variety of 3-(1-methylpyrrolidin-2-yl)-4-(alkyl, aromatic, heterocyclic and silanyl) and -N-alkyl pyridines were synthesized (compounds 1–9). In vial tests with the green peach aphid, Myzus persicae, compounds 1–4 were 1.1, 1.8, 2.3 and 1.9×, respectively, more active than nicotine and 64, 40, 31 and 38×, respectively, less active than acetamiprid. Against the western flower thrips, Frankliniella occidentalis, 1–4 were 1.4, 2.1, 2.0 and 1.6×, respectively, more active than nicotine and 9, 6, 6 and 8×, respectively, less active than acetamiprid. For the cotton aphid, Aphis gossypii, the activity of 1–9 was similar to nicotine. Compounds 7 and 9 when incorporated into artificial diet produced low mortality for larvae of the beet armyworm, Spodoptera exigua, but were not active against the corn earworm, Helicoverpa zea. When 1–4 and 6–9 were injected into larvae of the beet armyworm, a variety of symptoms similar to acetamiprid were observed which included tremors, uncoordinated movement, diuresis, paralysis and death. In addition, imidacloprid-binding to membranes from the house fly head, Musca domestica, was inhibited by compounds 1–9, when using a concentration range of 1–100 μM. These studies demonstrate that our new chemistry enhances the insecticidal activity of nicotine with an apparent mode of action as an acetylcholine agonist.

Two approaches to the aza-tricyclo dodecane skeleton of (-)-FR901483 are reported. Both routes utilized a Grignard addition to an N-acylpyridinium salt to establish the absolute stereochemistry at C-6 and a highly diastereoselective conjugate allylation reaction to form the quaternary center at C-1 of the natural product in an excellent yield. Although the desired polysubstituted piperidine intermediates were prepared regio- and stereoselectively, the construction of the C-8/C-9 bond connectivity could not be achieved. All attempts at a pinacol cyclization or an intramolecular 6-exo-tet epoxide opening were unsuccessful because of an unfavorable A(1,3) strain inherent in the molecule.

[reaction: see text] A six-step synthesis of (S)-brevicolline from (S)-nicotine is reported. Regioselective trisubstitution of the pyridine ring of nicotine, followed by successive Suzuki cross-coupling and Buchwald amination reactions, afforded the enantiopure beta-carboline alkaloid, brevicolline.

[chemical reaction: see text]. Sequential tandem directed lithiations of an N-Boc-4-methoxy-1,2-dihydropyridine have been achieved, leading to C-5,C-6 disubstituted dihydropyridones on acidic workup. The chlorine atom of the dihydropyridone products can in turn be substituted giving rise to diverse substituents at C-6.

[reaction: see text] A variety of novel nicotine derivatives were prepared from (S)-nicotine via a two-step sequence. Addition of a cuprate reagent to an N-acylpyridinium salt of nicotine, followed by aromatization with elemental sulfur, afforded C-4 substituted nicotines in moderate to high yield. Using this method, 4-(dimethylphenylsilyl)nicotine was prepared and oxidized to afford (S)-4-hydroxynicotine.

Synthesis of novel heterocycles, which contain the unique 10-oxa-1,8-diazaanthracen-9-one tricyclic core, is reported. The core structure was assembled via a dehydrative-cyclization strategy.

The asymmetric total synthesis of natural (+)-cannabisativine 1 was completed in 19 steps and 7% overall yield. The key synthetic intermediate 29 was prepared with a high degree of stereocontrol in 12 steps starting from chiral 1-acylpyridinium salt 10. Addition of zinc enolate 11 to pyridinium salt 10 furnished dihydropyridone 12 containing two contiguous stereocenters of the correct absolute configuration. Luche reduction of ketone 16 afforded diol 17 in high yield (96%) and excellent diastereoselectivity. The Mukaiyama−Michael reaction of pyridones 27a/b with O-silyl ketene acetal 32 gave phenyl selenyl ketones 33a/b with complete stereoselectivity. Elimination of cis-β-hydroxyselenides 34 and 35 effected the regiocontrolled preparation of tetrahydropyridine derivative 29. Several approaches to the macrocyclic ring closure of the 13-membered ring were investigated, ultimately leading to the completion of an asymmetric synthesis of the target compound with a high degree of stereocontrol.

[reaction: see text] A strategy for the synthesis of the spirocyclic core of spirolucidine was explored through a model study. The diene 4a was prepared and photolyzed to give the desired [2 + 2] photoadduct 17 containing the correct relative stereochemistry corresponding to spirolucidine.

Dihydropyridones of the type 1 were converted to their C-5 alkylidene derivatives 2 by a reaction sequence involving phosphorylation, conjugate reduction or addition to provide piperidones 4, and then olefination via a Horner–Wadsworth–Emmons reaction. An intramolecular version of this method was used to prepare trans-bicyclic enone 13.

A concise synthesis of (S)-macrostomine has been accomplished in five steps from natural nicotine in 19% overall yield via a pyridyne Diels-Alder cycloaddition reaction as the key step. A Kumada cross-coupling reaction on a 1-chloroisoquinoline intermediate provided the natural product.

An iodocyclocarbamation procedure has been developed for the stereoselective preparation of erythro - and threo -2-(1-hydroxyalkyl)piperidines. This methodology was utilized in the asymmetric synthesis of two piperidine alkaloids, (+)-α-conhydrine and (+)-β-conhydrine.

Multisubstituted piperidines containing a trimethylsilylmethyl group at C-2 can be opened regioselectively with TBAF and cyanogen bromide. The ring-opened products contain synthetically useful cyanamide and terminal alkene functional groups. This method is useful for the stereoselective synthesis of alkylamine derivatives containing multiple chiral centers.

Commercially available (S)-nicotine was converted in two or three synthetic steps to various chiral amino alcohols. These nicotine derivatives were evaluated as potential chiral ligands for metal-catalyzed asymmetric reactions by using the addition of diethylzinc to aldehydes as a screen. Several reactions proceeded with a high degree of enantioselectivity providing good yields of secondary alcohols of high enantiopurity.

Nucleophilic addition of organometallics to chiral 1-acylpyridinium salts occurs with high diastereoselectivity to give N-acyl-2,3-dihydro-4-pyridones, which are useful building blocks for the asymmemc synthesis of various alkaloids. The synthetic utility of these heterocycles lies in the ease of preparation and substitution. Our recent efforts at exploring the scope of this chemistry and its application towards the enantioselective synthesis of various alkaloids are described.

Multisubstituted piperidines containing a phenyl group at C-2 can be opened regio- and stereoselectively with cyanogen bromide. The ring-opened products contain useful cyanamide and benzylic bromide functional groups. This methodology is useful for the stereoselective synthesis of uniquely substituted alkylamine derivatives containing multiple chiral centers and various functionality.

Stereoselective acetoxylation at the C-3 position of N-acyl-2-alkyl-2,3-dihydro-4-pyridones was effected with Pb(OAc) 4 in refluxing toluene.

The photocycloaddition of enantiopure bis-dihydropyridone 4 provided a single cycloadduct in high yield. Treatment of the cycloadduct with SmI2 effected ring opening and intramolecular aldol addition to give pentacyclic β-hydroxyketone 7.

Altinicline (SIB-1508Y), an anti-Parkinson's agent, was prepared in five steps from natural nicotine in 32% overall yield via a regioselective substitution of the pyridine ring of (S)-nicotine.

Lithium–halogen exchange of 2,4-dibromoquinolines proceeds regioselectively at C-4 and affords 4-substituted quinolines on quenching with electrophiles. Palladium-catalyzed cross-coupling reactions of 2-bromo-4-iodoquinoline provide 4-substituted 2-bromoquinoline derivatives.

A simple two-step procedure converts 2-substituted N-acyl-2,3-dihydro-4-pyridones to 2,4-disubstituted N-acyl-5,6-dihydro-2-pyridones.

Various cyclohexyl-based chiral auxiliaries were studied for their effectiveness in the chiral 1-acylpyridinium salt/Grignard reaction.

Intramolecular Heck reactions of N-acyl-2,3-dihydro-4-pyridones provide polycyclic heterocycles with high regio- and stereoselectivity.

The preparation and application of dihydropyridines continue to attract considerable interest in organic synthesis and medicinal chemistry. The biological activities and synthetic utility of these heterocycles have prompted the development of new routes to their construction. The Hantzsch synthesis of dihydropyridines and pyridines has been well-studied and is now a very reliable method for preparing numerous symmetrical and asymmetrical derivatives. A widely used method to prepare 1,2- and 1,4-dihydropyridines involves the addition of nucleophiles to N -activated pyridines. The regioselectivity of this reaction has been shown to be dependent upon the pyridine-activating reagent and the nucleophile. Numerous catalytic methods for the construction of dihydropyridines have been developed. This review covers recent contributions to the preparation of dihydropyridines and pyridines via acyclic and cyclic precursors, the conversion of dihydropyridine intermediates to pyridines, and the synthetic utility of dihydropyridines as synthetic intermediates in organic synthesis.

This chapter describes total syntheses from Professor Comins' laboratories using chiral N -acylpyridinium salt chemistry and N -acyl-2,3-dihydro-4-pyridone building blocks. These dihydropyridones are ideal synthetic intermediates due to their facile preparation from pyridine derivatives, the useful functionality present, their availability as either enantiomerically pure isomer, good air and acid stability, ease of introducing ring substituents in a regio- and stereocontrolled fashion, and their potential for use in alkaloid synthesis. Application of this chemistry towards the concise, asymmetric total syntheses of twenty four alkaloids of various types are included along with mechanistic explanations for the observed stereoselectivity of many key reactions.

The C-5 position of N-Acyl-2-alkyl-2,3-dihydro-4-pyridones can be substituted by halogenation followed by a cross-coupling or carbonylation reaction.

The oxidation of silyl enol ethers 2 with palladium(II) acetate is a convenient method for the preparation of synthetically useful 2,6-disubstituted 2,3-dihydro-4-pyridones 3.

The DE ring camptothecin intermediate II was prepared enantioselectively in six steps from 2-fluoropyridine using a pyridine ȁhalogen-danceȁ reaction.