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Many bacterial pathogens, including Staphylococcus aureus, require inosine 5'-monophosphate dehydrogenase (IMPDH) for infection, making this enzyme a promising new target for antibiotics. Although potent selective inhibitors of bacterial IMPDHs have been reported, relatively few have displayed antibacterial activity. Here we use structure-informed design to obtain inhibitors of S. aureus IMPDH (SaIMPDH) that have potent antibacterial activity (minimal inhibitory concentrations less than 2 μM) and low cytotoxicity in mammalian cells. The physicochemical properties of the most active compounds were within typical Lipinski/Veber space, suggesting that polarity is not a general requirement for achieving antibacterial activity. Five compounds failed to display activity in mouse models of septicemia and abscess infection. Inhibitor-resistant S. aureus strains readily emerged in vitro. Resistance resulted from substitutions in the cofactor/inhibitor binding site of SaIMPDH, confirming on-target antibacterial activity. These mutations decreased the binding of all inhibitors tested, but also decreased catalytic activity. Nonetheless, the resistant strains had comparable virulence to wild-type bacteria. Surprisingly, strains expressing catalytically inactive SaIMPDH displayed only a mild virulence defect. Collectively these observations question the vulnerability of the enzymatic activity of SaIMPDH as a target for the treatment of S. aureus infections, suggesting other functions of this protein may be responsible for its role in infection.

γ-Irradiation of crystalline hexaaquamagnesium trans-2-butenoate dihydrate affords rel-(3S,4R)-1-hexene-3,4-dicarboxylate by a single-crystal-to-single-crystal reaction. The reaction proceeds by a ...

Many bacterial pathogens, including Staphylococcus aureus, require inosine 5’-monophosphate dehydrogenase (IMPDH) for infection, making this enzyme a promising new target for antibiotics. Although potent selective inhibitors of bacterial IMPDHs have been reported, relatively few have displayed antibacterial activity. Here we use structure-informed design to obtain inhibitors of S. aureus IMPDH (SaIMPDH) that have potent antibacterial activity (minimal inhibitory concentrations less than 2 μM) and low cytotoxicity in mammalian cells. The physicochemical properties of the most active compounds were within typical Lipinski/Veber space, suggesting that polarity is not a general requirement for achieving antibacterial activity. Five compounds failed to display activity in mouse models of septicemia and abscess infection. Inhibitor-resistant S. aureus strains readily emerged in vitro. Resistance resulted from substitutions in the cofactor/inhibitor binding site of SaIMPDH, confirming on-target antibacterial activity. These mutations decreased the binding of all inhibitors tested, but also decreased catalytic activity. Nonetheless, the resistant strains had comparable virulence to wild-type bacteria. Surprisingly, strains expressing catalytically inactive SaIMPDH displayed only a mild virulence defect. Collectively these observations question the vulnerability of the enzymatic activity of SaIMPDH as a target for the treatment of S. aureus infections, suggesting other functions of this protein may be responsible for its role in infection.

The structure of (±)-clavilactone D was revised, and the synthesis was achieved in seven steps from a substituted benzaldehyde. The key step was the base-catalyzed cyclization of an α,β-carbonyl peroxide, which was obtained by an iron-catalyzed three-component reaction of a benzaldehyde, an alkene, and TBHP. NaBH4-mediated reductive lactonization of the resulting cis-dicarbonyl epoxide led to the α,β-epoxy-γ-butyrolactone skeleton highly stereoselectively. The synthesis provides a concise, reliable, and practical route to the revised structure of clavilactone D.

Mycobacterium tuberculosis (Mtb) is the world's most deadly pathogen. Unlike less virulent mycobacteria, Mtb produces 1-tuberculosinyladenosine (1-TbAd), an unusual terpene nucleoside of unknown function. In the present study 1-TbAd has been shown to be a naturally evolved phagolysosome disruptor. 1-TbAd is highly prevalent among patient-derived Mtb strains, where it is among the most abundant lipids produced. Synthesis of TbAd analogs and their testing in cells demonstrate that their biological action is dependent on lipid linkage to the 1-position of adenosine, which creates a strong conjugate base. Furthermore, C2O lipid moieties confer passage through membranes. 1-TbAd selectively accumulates in acidic compartments, where it neutralizes the pH and swells lysosomes, obliterating their multilamellar structure. During macrophage infection, a 1-TbAd biosynthesis gene (Rv3378c) confers marked phagosomal swelling and intraphagosomal inclusions, demonstrating an essential role in regulating the Mtb cellular microenvironment. Although macrophages kill intracellular bacteria through phagosome acidification, Mtb coats itself abundantly with antacid.

In this experiment, students carry out a modern organocatalytic reaction using IMes·HCl and NaOH to catalyze the formation of 1,3,4-triphenylcyclopentene from cinnamaldehyde and chalcone in water. Deprotonation of IMes·HCl with NaOH forms the N-heterocyclic carbene IMes that reacts with cinnamaldehyde to form a homoenolate equivalent of cinnamate, which undergoes a conjugate addition to chalcone followed by an intramolecular aldol reaction to form a cyclopentane. Formation of a β-lactone and decarboxylation leads to 1,3,4-triphenylcyclopentene. This reaction introduces students to both organocatalysis and the use of carbonyl anion and homoenolate equivalents in synthesis. This novel and interesting chemistry was first reported in 2006, and the reaction was modified to be carried out in water under an air atmosphere in 2013. The very nonpolar product is easily purified chromatographically. The aliphatic protons form a somewhat complex pattern due to allylic and homoallylic coupling, but with no overlap, so...

Hydrogenation (3 atm) of readily available pyrido[1,2-a]pyrimidines 10, 14, and 17 over 5% Rh/Al2O3 forms 1,5-diazabicyclo[4.4.0]dec-5-enes 9, 15, and 18 in >95% yield, providing a general route to this little-studied class of compounds. All attempts to form the tetrahydro-1,2,4-triazine moiety of cinachyramine (1) by rearrangement of amidinium dimethylhydrazone 8 using the procedures developed by Kamatori to convert hydrazone 3a to tetrahydro-1,2,4-triazine 4a were unsuccessful.

Although small molecules shed from pathogens are widely used to diagnose infection, such tests have not been widely implemented for tuberculosis. Here we show that the recently identified compound, 1-tuberculosinyladenosine (1-TbAd), accumulates to comprise >1% of all Mycobacterium tuberculosis lipid. Invitro and invivo, two isomers of TbAd weredetected that might serve as infection markers. Using mass spectrometry and nuclear magnetic resonance, we established the structure of the previously unknown molecule, N(6)-tuberculosinyladenosine (N(6)-TbAd). Its biosynthesis involves enzymatic production of 1-TbAd by Rv3378c followed by conversion to N(6)-TbAd via the Dimroth rearrangement. Intact biosynthetic genes are observed only within M.tuberculosis complex bacteria, and TbAd was not detected among other medically important pathogens, environmental bacteria, and vaccine strains. With no substantially similar known molecules in nature, the discovery and invivo detection of two abundant terpene nucleosides support their development as specific diagnostic markers of tuberculosis.

In this experiment, students carry out a halogen–metal exchange reaction of methyl 2-iodobenzoate with isopropylmagnesium chloride in THF at 0 °C to afford 2-carbomethoxyphenylmagnesium chloride, which is treated with p-methoxybenzaldehyde to give a lactone (phthalide) product. This reaction introduces students to the modern method of preparation of Grignard and organolithium reagents by halogen–metal exchange rather than by using metallic magnesium or lithium, which is rarely done in a research laboratory. It also demonstrates that Grignard reagents bearing reactive functionality can be prepared and utilized in synthesis, although students are still often taught otherwise. The IR spectrum of the crude product provides semiquantitative information on the success of the reaction because the lactone product and starting material ester and aldehyde have very different carbonyl absorptions, demonstrating the power of this technique to distinguish between functional groups. The product can be purified by chrom...

To identify lipids with roles in tuberculosis disease, we systematically compared the lipid content of virulent Mycobacterium tuberculosis with the attenuated vaccine strain Mycobacterium bovis bacillus Calmette-Guerin. Comparative lipidomics analysis identified more than 1,000 molecular differences, including a previously unknown, Mycobacterium tuberculosis-specific lipid that is composed of a diterpene unit linked to adenosine. We established the complete structure of the natural product as 1-tuberculosiny-ladenosine (1-TbAd) using mass spectrometry and NMR spectroscopy. A screen for 1-TbAd mutants, complementation studies, and gene transfer identified Rv3378c as necessary for 1-TbAd biosynthesis. Whereas Rv3378c was previously thought to function as a phosphatase, these studies establish its role as a tuberculosinyl transferase and suggest a revised biosynthetic pathway for the sequential action of Rv3377c-Rv3378c. In agreement with this model, recombinant Rv3378c protein produced 1-TbAd, and its crystal structure revealed a cis-prenyl transferase fold with hydrophobic residues for isoprenoid binding and a second binding pocket suitable for the nucleoside substrate. The dual-substrate pocket distinguishes Rv3378c from classical cis-prenyl transferases, providing a unique model for the prenylation of diverse metabolites. Terpene nucleosides are rare in nature, and 1-TbAd is known only in Mycobacterium tuberculosis. Thus, this intersection of nucleoside and terpene pathways likely arose late in the evolution of the Mycobacterium tuberculosis complex; 1-TbAd serves as an abundant chemical marker of Mycobacterium tuberculosis, and the extracellular export of this amphipathic molecule likely accounts for the known virulence-promoting effects of the Rv3378c enzyme.

A short and efficient synthesis of model spiroiminals that have the same stereochemistry but different conformations than marineosins A and B was carried out in 6-7 steps from 6-methyltetrahydropyran-2-one. These spiroiminals were also prepared biomimetically by reduction of an enol ether. A more highly substituted spiroiminal with the same stereochemistry and conformation as marineosin A was prepared in 11 steps from 6-methyl-4-propyl-3-phenyltetrahydropyran-2-one. A macrocyclic pyrrole lactone was prepared stereospecifically in 10 steps. A five step sequence converted the lactone to a late hemi-iminal intermediate that has resisted the methylation and spiroiminal formation that would lead to marineosin A.

A six step synthesis of (±)-7-hydroxylycopodine has been achieved in 5% overall yield. In the key step, a Prins cyclization of a bicyclic keto alkyne in 60% H(2)SO(4) forms a tricyclic dihydroxy amino ketone.

60Co γ-irradiation of bis(trans-2-butenoato)calcium (4) and triaquabis(trans-2-butenoato)magnesium (11) affords cyclodimerization products cis,trans- and trans,trans-nepetic acids (5 and 15), respectively. The products are produced in high yield, based upon conversion, by a γ-ray induced radical chain pathway and provide unprecedented, stereospecific, one-pot syntheses of two of the four possible nepetic acid diastereomers, adding significant generality to the synthetic scope of the γ-ray induced reactions of crystalline metal trans-2-butenoates. Stereochemical analysis of the products from the analogous trans-2-butenoato-3-d complexes 19 and 27 establishes unequivocally that hydrogen atom transfer is also stereospecific and not part of a random process. The stereochemistry of the diastereomers is that predicted by the analysis of crystal packing, consistent with the least-motion principles of the topochemical postulate. Analysis of the crystal structures, with respect to the nearest neighbors, is consistent with the hypothesis that the formation of both carbon–carbon bonds and hydrogen atom transfer are topochemical and controlled by the crystal lattice. Analysis of the packing diagrams provides a pathway for chain propagation throughout the crystal that consumes all the molecules in the unit cell.

Reaction of 6-chloro-2-fluoro-3-pyridineacetamide with 1,2-bis(trimethylsilyloxy)cyclobutene in ether saturated with hydrogen chloride afforded the keto amide in 85% yield. In the key step, treatment of the keto amide with aqueous KOH in t-BuOH resulted in a tandem intramolecular aldol reaction-intramolecular nucleophilic aromatic substitution sequence to give the tetracylic lactam in 46% yield. Reduction of the lactam with BH(3) in THF gave phantasmidine in 67% yield.

A convergent, practical route to unstable hexacyclic parnafungin A and C models has been developed. Two iodoxanthones were prepared in four or five steps (33-50% overall yield). Suzuki-Miyaura coupling of the iodoxanthones with excess readily available 3-carbomethoxy-2-nitrophenyl pinacol boronate afforded the hindered highly functionalized 2-arylxanthones (53-58%) in the first key step. In the second key step, zinc reduction gave benzisoxazolinones that were treated with MsCl and then base to generate the unstable hexacyclic parnafungin A (13% overall yield for 8 steps) and C (8% overall yield for 9 steps) models. Analogously to the parnafungins, hexacyclic parnafungin C model decomposes to a phenanthridine with a half-life of 2 d in CDCl(3).

Dinemasone C was prepared in three steps (8% overall yield) from cis-tetrahydro-4-hydroxy-6-methyl-2-pyrone by aldol reaction with 2,4-hexadienal, epoxidation followed by cyclization, and epimerization of the ring fusion. Dinemasone C, epi-dinemasone C, anhydrodinemasone BC, and nor-dinemasone B are active against bacteria, including Legionella pneumophila Corby, algae, and fungi.

Me(2)AlCl-catalyzed Diels-Alder reaction of N-tigloyloxazolidinone with 6,6-dimethyl-1-vinylcyclohexene selectively provided the exo adduct, which was converted to nosyberkol (isotuberculosinol) and tuberculosinol. The spectral data for nosyberkol are identical with those reported for edaxadiene, whose structure is revised accordingly.

Esterification of the trienoic acid with o-xylylene dibromide gave the bis ester that underwent a templated Diels-Alder reaction to afford the macrodiolide stereospecifically in a single step. The synthesis of bistellettadine A was completed in four steps by hydrolysis and side chain elaboration.

An asymmetric Diels-Alder reaction between acrolein and 1-benzyloxymethyl-1,3-cyclohexadiene affords a bicyclic aldehyde that was elaborated in 11 steps to nor-platencin. nor-Platencin is 4-16 times less active than platencin against several resistant strains of Staphylococcus aureus, macrolide-resistant Enterococcus faecalis, and vancomycin-resistant Enterococcus faecium.

Addition of guanidine to a 6-methylhexahydroindenone in MeOH at 85 degrees C afforded 7-epineoptilocaulin. A similar reaction with a 6-propylhexahydroindenone afforded netamine E. MnO2 oxidation of 7-epineoptilocaulin and netamine E afforded mirabilin B and netamine G, respectively. The netamines have the side chains trans, not cis as was initially proposed. A unified biosynthetic scheme for the batzelladines and ptilocaulin family is proposed. Conjugate addition of guanidine to a bis enone followed by an intramolecular Michael reaction of the enolate to the other enone, aldol reaction, dehydration, and enamine formation will lead to a tricyclic intermediate at the dehydroptilocaulin oxidation state. 1,4-Hydride addition will lead to ptilocaulin or 7-epineoptilocaulin depending on which face the hydride adds to. 1,2-Hydride addition will lead to isoptilocaulin. The key tricyclic intermediate was prepared from a tetrahydroindenone and guanidine and reduced with NaBH4 to give a mixture rich in ptilocaulin and isoptilocaulin.

Mander reductive alkylation of methyl 2-methoxybenzoate with prenyl bromide and hydrolysis of the enol ether afforded methyl 6-oxo-1-prenyl-2-cyclohexenecarboxylate. This was converted in five steps (reduction of the ketone, saponification, iodolactonization, ozonolysis, and intramolecular aldol reaction) to a spiro lactone cyclopentenal. An efficient first synthesis of (+/-)-vibralactone was completed by retro-iodolactonization with activated Zn, formation of the beta-lactone (vibralactone C), and reduction of the aldehyde. Except for the novel use of an iodolactone to protect both the prenyl double bond and carboxylic acid, no protecting groups were used. A similar sequence starting with asymmetric reductive alkylation of the (2S)-2-methoxymethoxymethylpyrrolidine amide of 2-methoxybenzoic acid with prenyl bromide afforded (-)-vibralactone confirming the absolute stereochemical assignment that was based on computational methods.

Reductive alkylation of methyl 2-methoxybenzoate with prenyl bromide and hydrolysis afforded methyl 6-oxo-1-prenyl-2-cyclohexenecarboxylate. Reduction of the ketone, hydrolysis, iodolactonization, ozonolysis, and intramolecular aldol reaction provided a spiro lactone cyclopentenal. Retro-iodolactonization with activated Zn, formation of the beta-lactone, and reduction of the aldehyde completed an efficient first synthesis of (+/-)-vibralactone. No protecting groups were used except for the novel use of an iodolactone to protect both the prenyl double bond and carboxylic acid.

Acid-catalyzed condensation of 2,6-dihydroxybenzoic acid 3 with ketal aldehyde 14 in methanol at 25 degrees C, followed by CH2N2 esterification, gave a 4:1:4:1 mixture of diastereomers 15b-18b in 60% yield. Equilibration of this mixture with TFA in CDCl3 provided tetracycle 15b (83% yield) with the complete skeleton of berkelic acid. A similar condensation at 0 degrees C afforded 15b-18b and a reduction product 19b, which was probably formed by a 1,5-hydride shift.

The homopolymerizations of a series of 3-n-alkyl-1-vinylimidazolium iodides are described in which the length of the quaternizing alkyl group was varied from methyl to n-propyl to n-hexyl to n-heptyl to n-dodecyl to n-hexadecyl. The preparations of these cationic monomers have previously been reported through reaction of 1-vinylimidazole with the corresponding n-alkyl iodide. All polymerizations were performed in aqueous solution at the same molar concentration of monomer using the free radical initiator 4,4′-azobis-4-cyanopentanoic acid. It was found that the short side-chain polyions (methyl and n-propyl) were water soluble, whereas the more hydrophobic intermediate side-chain polyions (n-hexyl and n-heptyl) were water insoluble. The long side-chain polyions (n-dodecyl and n-hexadecyl), on the other hand, being highly hydrophobic, appeared to form polysoaps and remained in aqueous solution. The solution behavior of these polyions in water, in aqueous salt solution, and in chloroform is discussed as well as is the critical micelle concentration of a long side-chain polyion and its corresponding monomer.

An efficient, stereospecific synthesis of the alkaloids senepodine G (2) and cermizine C (1) has been completed using the BF3.Et2O-promoted stereospecific addition of Me2CuLi to alpha,beta-unsaturated lactam 6 to provide lactam 3, the addition of MeMgBr followed by HCl to convert 3 to senepodine G (2) (six steps, 40% overall yield), and the stereospecific NaBH4 reduction of 2 to give cermizine C (1) (seven steps, 40% overall yield).

Hydrogenation of readily available pyrido[1,2-a]pyrimidinium salts (I) over a Rh-catalyst forms title compounds (II) in high yields, providing a general route to this little-studied class of compounds.

Crisscross cycloaddition of citronellal azine (6) with 2 equiv. of TFA and powdered 3 Å molecular sieves in CH2Cl2 at reflux for 22 h afforded 37% of the desired C2-symmetric hydrazine 7 and 5%–10% of diastereomer 8 in which one of the 6–5 ring fusions is cis. Methylation of the hydrazine of 7 and reduction of the resulting salt (9) with Li in NH3 cleaved the N—N bond to give secondary tertiary amine 10 in 97% yield. Eschweiler–Clarke methylation afforded the C2-symmetric bis tertiary amine 11 in 69% yield. Racemic products were obtained in initial attempts at asymmetric catalysis using 7 or 11 as asymmetric bases, using bistertiary amine 11 as a ligand analogous to sparteine for alkyllithiums, or using the lithium amide from secondary tertiary amine 10 as an asymmetric base. Apparently, the proton is buried in the core of 11, leaving a hydrophobic surface; the free counterion is not an asymmetric catalyst. Diamine 11 may be too hindered to complex to s-BuLi. Tertiary amine 11 (pKa1 = 24.7) is more basic than DBU (pKa = 24.3) in CH3CN, in good agreement with theory.Key words: crisscross cycloaddition, azine, dipolar cycloaddition, calculation of pKa.

Reaction of pyranulose 6 with styrenes 12c or 13 and Et3N in CH2Cl2 at 25 °C afforded the [5+2] cycloadducts 14c and 15, which were hydrolyzed to give the natural products 1 and descurainin (2) in 24 and 27% overall yield, respectively. Heating pyranulose 6 with cinnamate ester 21 in the presence of 2,6-di-t-butylpyridine in CH3CN at 175 °C afforded the [5+2] cycloadduct, which was hydrolyzed to give cartorimine (3) in 13% yield.

[structures: see text] Epohelmins A (24) and B (26) have been reassigned as pyrrolizidin-1-ols, rather than the proposed 9-oxa-4-azabicyclo[6.1.0]nonane structures 1 and 2, respectively. Syntheses of epohelmin A (24) (eight steps, 52% overall yield) and epohelmin B (26) (11 steps, 43% overall yield) have been achieved starting from N-Cbz-(S)-prolinal (9) and ortho ester ketone 17 using a stereoselective aldol reaction and a stereoselective reductive cyclization as the key steps.

Condensation of hydroxypyridone 7 with ethyl pyruvate and p-chlorothiophenol, reduction, and cyclization afforded 77% of lactone 6. Protection of the pyridone, acylation of the enolate with tigloyl chloride, and deprotection provided keto lactone 22. Reduction and dehydrative cyclization completed short and efficient syntheses of 2 and 3.

The methionine salvage pathway allows the in vivo recovery of the methylthio moiety of methionine upon the formation of methylthioadenosine (MTA) from S -adenosylmethionine (SAM). The Fe(II)-containing form of acireductone dioxygenase (ARD) catalyzes the penultimate step in the pathway in Klebsiella oxytoca , the oxidative cleavage of the acireductone 1,2-dihydroxy-3-oxo-5-(methylthio)pent-1-ene ( 2 ) by dioxygen to give formate and 2-oxo-4-(methylthio)butyrate ( 3 ). The Ni(II)-bound form (Ni–ARD) catalyzes an off-pathway shunt, forming 3-(methylthio)propionate ( 4 ), carbon monoxide, and formate. Acireductone 2 is formed by the action of another enzyme, E1 enolase/phosphatase, on precursor 1-phosphonooxy-2,2-dihydroxy-3-oxo-5-methylthiopentane ( 1 ). Simple syntheses of several analogs of 1 are described, and their activity as substrates for E1 enolase/phosphatase characterized. A new bacterial overexpression system and purification procedure for E1, a member of the haloacid dehalogenase (HAD) superfamily, is described, and further characterization of the enzyme presented.

The radicals formed in Mn(III)-based oxidative free-radical cyclizations of beta-keto esters and malonate esters can be trapped with sodium azide and Mn(III) to give cyclic and bicyclic azides in 30-80% yield. Reduction of the azide gives bi- and tricyclic lactams. [reaction: see text]

EtAlCl(2)-induced cyclization of chiral gamma,delta-unsaturated ketones 11c and 17b takes place mainly from the expected face. The selectivity is modest for 11c (60:40) in which the large substituent is a primary alkyl group and the medium substituent is a methyl group and excellent for 17b (93:7) in which the large substituent is a cyclohexyl group and the medium substituent is a methyl group. The cyclization of 17a is anomalous, suggesting that the phenyl group has more than a simple steric effect.

O -Alkylation of N -hydroxycarbamate 6 with iodo ester 5 affords 15 , which was elaborated to mesylate 4 . Intramolecular N -alkylation affords methyl N -Boc-4-methyl-1,2-oxazetidine-4-carboxylate ( 3 ). The geminal coupling constant of the methylene protons is 8.5 Hz, which is much smaller than the 12.0 Hz reported for halipeptins A and B. This confirms that the halipeptins do not contain an oxazetidinecarboxylic acid as originally proposed in structure 1 , but a thiazoline as in the revised structure 2 . The unusual O -alkylation of 5 probably proceeds by an electron transfer mechanism.

[structure: see text] The structure of waol A has been revised from 1 to 6, the vinylogue of TAN-2483 A (5). Aldol reaction of 10b(c) with 2,4-hexadienal (11) affords 9b(c), which is subjected to iodoetherification with bis(sym-collidine)IPF(6) to provide 8b(c). Treatment with Et(3)N in CH(2)Cl(2) completes three-step syntheses of TAN-2483A (5) and waol A (6).

Reaction of α-unsubstituted nitroacetates with Mn(OAc)3 gives mixtures of isoxazolines, formed by dehydration to a nitrile oxide that undergoes cycloaddition, and isoxazoline oxides or cyclopropane, formed by oxidative cyclization. Oxidative cyclization is favored with electron-rich alkenes and cycloaddition with the nitrile oxide to give isoxazolines is favored with electron-poor alkenes. On the other hand, α-substituted nitroacetates cannot dehydrate and undergo only radical reactions.

Oxidative cyclization of unsaturated Meldrum's acids can be carried out at temperatures as low as −30°C. The rate-determining step is cyclization of the enolate to the alkene ( 11 to 14 and 15 ) rather than enolization, which is the rate-determining step with dimethyl 4-pentenylmalonate ( 1 ). While cyclization of 1 gives mainly cyclopentanes, cyclization of Meldrum's acids provides a versatile route to cyclohexenes.

2,2,6,6-Tetramethylpiperidine (TMP)-catalyzed (1–10%) chlorinations of phenols by SO2Cl2 in aromatic solvents are more ortho selective than with primary and less hindered secondary amine catalysts. Ortho-selective chlorination is successful even with electron deficient phenols such as 2-hydroxybenzaldehyde and 2′-hydroxyacetophenone. Notably, ortho selectivity increases with the reaction temperature. On the other hand, tetraalkylammonium chloride-catalyzed chlorinations are moderately para selective.

Aldehydes and ketones react with alkenes either thermally or in the presence of Bronsted or Lewis acids to afford either Prins or ene products. This chapter covers advances in this area since the publication of the first edition of COS in 1991. Intermolecular ene reactions of formaldehyde, chloral, fluoral, glyoxylate esters, aliphatic and aromatic aldehydes, ketones, and electron-deficient ketones such as pyruvate esters are broadly useful. Thermal and Lewis acid-catalyzed intramolecular type I ene reactions leading to 2-alkenylcyclopentanols and cyclohexanols and type II ene reactions leading to 3-methylenecyclohexanols and cycloheptanols provide a general route to these ring systems. Intramolecular Prins reactions are useful for the preparation of functionalized cycloalkanols. Alkoxonium cations undergo oxonium ene reactions and Prins cyclizations that provide a general route to substituted tetrahydropyrans. The ene reactions of imines and thiocarbonyl compounds are also covered. Major advances that have been made since the first edition was published include asymmetric intermolecular ene reactions of electron-deficient aldehydes and ketones, Prins cyclizations, and Prins-pinacol reactions.

A new annelation procedure has been developed in a model system to introduce the cyclohexene ring of guanacastepene. Cyclohexenone 16 is prepared by sequential methylation and alkylation with allylic iodide 15 . One-pot epoxidation, protodesilylation and hydrolysis of the THP forms dione 19 , which cyclizes with NaOMe to 24 in 57% overall yield. Reduction, Mitsunobu inversion, and selective oxidation of the primary alcohol forms model 29 . Phenyldimethylsilyl allylic iodide 36 is easier to make and more stable than trimethylsilyl allylic iodide 6 used by Stork.

[see structure]. A 16-step synthesis of the novel cytotoxin salicylihalamide A (1E) has been achieved in 3.3% overall yield using ring closing metathesis to generate the macrolide and addition of (1Z,3Z)-hexadienylcuprate (2), which was generated in situ from ethylcuprate and acetylene, to alkenyl isocyanate 3 to form the side chain.

The Eguchi aza Wittig protocol has been used for the synthesis of sclerotigenin and circumdatin F by selective acylation of the more acidic anilide nitrogen of a benzodiazepinedione without the need for protecting groups. The use of the 2-nitrobenzyl group as a photochemically labile protecting group for the amide nitrogen of a diketopiperazine permits the use of the aza Wittig procedure for the synthesis of fumiquinazoline G.

Hindered guanidines can be prepared by reaction of cyanamides with amines in hexafluoroisopropanol at 90–120°C. This sequence was used for preparing guanidinium acid 21 as a model for martinellic acid.

Condensation of aldehyde 3a with hydroxylamine 4b afforded nitrone 2, which underwent an intramolecular cycloaddition to give 1b, the proposed structure of pyrinodemin A. A similar condensation of aldehyde 3a and hydroxylamine 4a provided pyrinodemin A (1a), which has the double bond one carbon further away from the isoxazolidine. An analogous sequence gave pyrinodemin B (21).

Condensation of pyridone 6 with enal 25 using DMAP in EtOH at 150°C afforded 8% of the desired Diels-Alder adduct 22, 8% of the bridged adduct 36 and 1–2% of a partially pure cis-fused adduct 37 of unknown stereochemistry. Hydroxylation of 22 completed a short synthesis of fusaricide (1).

Reaction of β-keto ester 12 with 2 equiv. of Mn(OAc)32H2O in KOAc-buffered MeOH followed by acidic workup afforded 51% of tricyclic furan 14 indicating that oxidative cyclizations can be terminated by addition to furans. Reduction of 14 with LAH provided 7, completing a five-step formal synthesis of 15-acetoxypallescensin-A.

Ceric ammonium nitrate oxidizes unsaturated ketene dithioacetals in wet MeCN to give cation radicals that cyclize to trisubstituted double bonds and styrenes by cation-like cyclizations leading to cyclic cation radicals that are transformed by further oxidation, hydrolysis and cyclization to bicyclic lactones in moderate to good yield.

The first total synthesis of the novel hepatotoxin (±)-cylindrospermopson (1) has been accomplished in 20 steps from 4-methoxy-3-methylpyridine (12) in 3.5% overall yield. The substituted piperidine A ring 19 was generated stereospecifically by a four-step sequence using the addition of trimethylsilylethynylmagnesium bromide to 12 to give 16 and stereospecific addition of vinylcuprate to 16 to form 17. The reaction of diamine 26 with cyanogen bromide produced the cyclic guanidine C ring of 27. The key step in the synthesis was bromination of ketone 31, followed by hydrogenation to liberate the free guanidine, which underwent an intramolecular SN2 reaction to form the tetrahydropyrimidine ring B of 32. Further hydrogenation reduced the ketone to yield 42% of 32 containing the fully functionalized tricyclic system and protected hydroxymethyluracil side chain of cylindrospermopsin. Hydrolysis of the pyrimidine in concentrated hydrochloric acid and selective monosulfation completed the synthesis of cylindrosp...