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Chemistry, Organic

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Biology, Microbiology and Chemistry, Organic

Pactamycin (1), a cytotoxic antibiotic produced by Streptomyces pactum, var. pactum, contains several interesting structural features, including a cyclopentanoid ring, which is rare among natural products, a 6-methylsalicylic acid (6-MSA) unit derived from acetate via a polyketide route, and a m-aminoacetophenone unit, which represents the m-C$\sb7$N unit found in many antibiotics. It was expected that 6-MSA would be an advanced precursor to the corresponding unit on pactamycin, but feeding experiments with 6-methyl (carboxy-$\sp $C) salicylic acid and methyl 6-methyl (carboxy-$\sp $C) salicylate failed to show significant incorporation into either pactamycin or its analogue pactamycate. In addition, these precursors were apparently toxic to S. pactum, causing pronounced acidification of the production medium and substantial reduction of pactamycin production.(DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI)

Chemistry, Organic

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Chemistry, Organic and Health Sciences, Immunology

The clinical success of conjugate anticancer and antiviral vaccines critically depends on the identification of, and access to, novel adjuvants with high potency and attenuated toxicity. The QS-21 fraction of Quillaja saponaria extracts comprises an isomeric mixture of complex triterpene saponins and is currently the most promising immunopotentiator in several antitumor and infectious disease vaccine therapies. However, the clinical use of QS-21 has been hindered by the difficulty in obtaining sufficient quantities of homogenous saponin from the natural source as well as by the low-grade toxicity and hydrolytic instability of this adjuvant. In this work, a robust chemical route to the two principal isomeric constituents of QS-21 has been established, and synthetically pure adjuvant has been prepared to fuel several pilot trials. In addition, an improved semisynthetic route to pure QS-saponin adjuvants has been developed, facilitating the discovery of novel immunostimulants with increased potency, stability and attenuated toxicity. This method was applied to the synthesis of the natural product adjuvant QS-7-Api and to non-natural aza-saponins. In this initial foray into designed molecular adjuvants, hydrolytically stable saponins have been discovered that equal or excel QS-21 as immunoadjuvants.

Chemistry, Organic

A general synthetic approach that affords both enantiomers of chiral lactones is described. The key step involves the automated multigram chromatography of diastereomeric derivatives of a racemic intermediate. The generality of the method is demonstrated by the synthesis of ring-saturated lactones of three different ring sizes, a series of bicyclic lactones, (alpha), (beta)-unsaturated lactones, and several examples containing aromatic substituents. Six of these examples occur in nature as pheromones or allomones, and hence are of biological interest. Assignments of absolute configuration to the lactone enantiomers and their precursors typically attend these syntheses. For some lactones, possessing suitable NMR spectra, direct determination of enantiomeric purity is possible using the chiral solvent (R)-(-)-2, 2, 2-trifluoro-1-(9-anthryl) ethanol.

Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

The kinetics of the reactions of alkyllithium reagents with ketones and esters in cyclohexane and benzene have been investigated by stopped-flow infrared spectroscopy at 25.0(DEGREES)C. A series of substituted phenyl-sec-butyl ketones (10a-i) and substituted ethyl benzoates (13a-i) along with several aliphatic ketones (14-17) and esters (18,19) were utilized in the study. These compounds were found to form coordination complexes with alkyllithium aggregates. Evidence for this was demonstrated by the appearance of a new carbonyl band in the infrared spectrum of a reacting solution of ester or ketone and alkyllithium reagent immediately after mixing. The new band, which is shifted to lower wave-number relative to the carbonyl band of the carbonyl compound, has been attributed to the formation of a substrate-alkyllithium aggregate complex in rapid equilibrium with the free substrate. Equilibrium constants (K(,c)) for complexation with sec-butyllithium in cyclohexane were determined for several compounds. A trend in the K(,c) values for the substituted phenyl-sec-butyl ketones and ethyl benzoates was observed: the more electron donating the substituent the larger the equilibrium constant of complexation. Further, larger K(,c) values were obtained for the esters, in their reactions with sec-butyllithium, than for the corresponding ketones.

Chemistry, Organic

The (alpha)-silyl-(beta),(gamma)-unsaturated esters were allowed to react with a variety of electrophiles in the presence of TiCl(,4), TiF(,4), BF(,3)(.)OEt(,2), FeCl(,3), or TMSOTf. Ethyl 2-trimethylsilyl-3-methyl-3-butenoate was used as a model substrate to examine the scope and limitations. In all cases, only products resulting from attack of the electrophile (aldehydes, ketones, acid chlorides, ketals, acetals, and chloromethyl phenyl sulfide) at the (gamma)-position were observed; no (alpha)-substituted products could be detected by GLC or ('1)H NMR. High stereoselectivity of ca. 9:1 around the 2,3-double bond is normally observed. Chloromethyl phenyl sulfide, an electrophile shown to give low (gamma):(alpha) ratios when reacted with silyl dienol ethers, also gives clean (gamma)-selectivity, albeit with lower stereoselectivity (E:Z ca 1:1). The model ester appears to have moderate reactivity, and fails to react with those electrophiles that cannot form a well-stabilized carbonium ion. The products isolated from the reactions of the model ester with electrophiles promoted by TiCl(,4), TiF(,4), or FeCl(,3) appeared, in some cases, to arise from subsequent conversion of the initially-formed adducts (chlorination, bis-substitution, and dimerization). In contrast, these further transformations were not observed with acetals and ketals employing TMSOTf as catalyst.

Chemistry, Organic

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Chemistry, Organic

Chloroperoxidase from Caldariomyces fumago has the characteristics of a promising industrial catalyst. Chloroperoxidase is inexpensive to produce and relatively stable and able to catalyze a large number of potentially useful reactions. However, the majority of the reactions studied occur with a lack of any enzyme induced stereoselectivity. Chloroperoxidase, in this report, is shown to catalyze the epoxidation reaction of a number of alkenes in a highly enantioselective manner with enantiomeric excesses between 50% and 97%. Good substrates were generally non-polar cis-alkenes of less than nine carbons in length. Unsubstituted terminal alkenes were shown to inactivate the enzyme. The recent determination of the three dimensional structure by x-ray crystallography and ongoing research in the development of an expression system for chloroperoxidase could open the door for a number of experiments concerning the mechanism of the epoxidation reaction. Also the possibility of improving the utility of chloroperoxidase in asymmetric epoxidations through directed evolution and site-directed mutagenesis remains an exciting prospect for the future.

Chemistry, Organic

There have been four mechanistic alternatives presented for the aryl bromide-alkyllithium exchange reaction: a four-centered transition structure mechanism; a single-electron mediated mechanism; an S$\sb{\rm N}$2 attack at bromine; and a pathway involving the formation of a bromine ate complex intermediate. The four-center mechanism proceeds with a small C-Br-C transition structure angle, whereas the S$\sb{\rm N}$2 and ate complex formation mechanisms proceed with a large C-Br-C angle. The single-electron transfer mediated mechanism involves dissociation to give bromide and therefore should not have a geometrical dependance in respect to a C-Br-C transition structure angle.

Chemistry, Inorganic and Chemistry, Organic

Osmium-chromium heterobimetallic complexes of the type (Y) (M(N)$\rm R\sb2(\mu$-O)$\rm\sb2CrO\sb2$) (Y = NBu$\sb4$, PPh$\sb4$; M = Os, Ru; R = Me, CH$\rm\sb2SiMe\sb3$, C$\rm\sb6H\sb5$) act as catalysts for the oxidation of primary and secondary alcohols to the corresponding aldehydes and ketones using dioxygen as the secondary oxidant. These complexes also catalyze the oxidation of 1,2-bis(diphenylphosphino)ethane (dppe) to the corresponding phosphine oxide, Ph$\sb2$P(O)CH$\rm\sb2CH\sb2P(O)Ph\sb2$. None of the singly oxidized phosphine is detected. Investigations into the kinetics of the oxidation reactions showed the oxidation of benzyl alcohol to benzaldehyde is first order in both alcohol and catalyst concentration. A mechanism involving coordination of the alcohol to the osmium center, followed by proton transfer and $\beta$-hydrogen elimination of the products yields a reduced osmium-chromium complex. This reduced complex can react with dioxygen to form a bridging peroxo complex that can react with a molecule of the reduced complex to regenerate two equivalents of the original heterobimetallic complex. Dioxygen labeling studies in the oxidation of dppe are described. Based on these experiments, two potential mechanisms are proposed for the oxidation of dppe. Routes toward the synthesis of a chiral version of the heterobimetallic catalyst utilizing a chiral counterion or an alkyl group derived from S-2-methylbutane, 2,2$\sp\prime$-dimethylbinaphthyl, camphene, 9,10-dibromocamphor and 2-norbornane are described.

Chemistry, Organic

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Chemistry, Organic

A systematic investigation of the mechanism and origin of stereoselection in the reaction of dioxane acetals with allyltrimethylsilane was undertaken. Experimental tests for two limiting mechanisms, synchronous (S$\sb{\rm N}$2-like) and dissociative (S$\sb{\rm N}$1-like) substitution processes, were investigated. The meso 2,4,6-trisubstituted 1,3-dioxane acetals provided an interesting opportunity to test the timing of bond breaking and making in the substitution reactions. The modest and C(2)-substituent-dependent selectivity excluded the possibility of direct S$\sb{\rm N}$2-type attack on a complexed acetal. Furthermore, when the allylation of a putative oxocarbenium ion was investigated only weak and inverted selectivity was observed, ruling out the intermediary of the extended separated ion in reactions of the cyclic acetals under similar conditions. A unified mechanistic scheme involving three distinct ion pairs is proposed to explain the dependence of allylation selectivity on structural and experimental variables. The three species: (1) an intimate ion pair, (2) an external ion pair, and (3) a separated ion each are proposed to react with a different stereochemical profile. The influence of C(2) substituent, acetal configuration, Lewis acid type and stoichiometry, nucleophile type and stoichiometry, concentration, solvent, and temperature were investigated and integrated in the proposed mechanistic scheme.

Chemistry, Organic

The stereoselective construction of $\beta$-hydroxy phosphonamidates could be accomplished through three main synthetic transformations. The first involves the acylation of various parent 1,3,2-oxazaphospholidines to provide monoalkylated $\beta$-keto phosphonamidates in good yield. The second step is the alkylation of the $\beta$-keto phosphonamidates to provide $\alpha,\alpha$-dialkylated $\beta$-keto phosphonamidates in high yield and very high diastereoselectivities. Finally, the highly diastereoselective reduction of the dialkylated $\beta$-keto phosphonamidates could be accomplished through the use of a variety of reducing agents to give $\beta$-hydroxy phosphonamidates in high yield and high diastereoselectivities.

Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

The transition state geometry for the transfer of oxygen from N-sulfonyl oxaziridines to alkenes and fluorine transfer from N-fluoro sultams to carbanions was investigated. In the former application of the endocyclic restriction test, a transition state model was developed, however, a model has not been constructed in the latter case. Although no transition state model has been constructed for the transfer of fluorine, the control experiments conducted indicate that this reaction is amenable to study using the endocyclic restriction test. The mechanism of hydrogen transfer from a benzylic or aryl carbon atom to organolithium reagents has been investigated by measuring intra- and intermolecular kinetic isotope effects. The results were more in line with a two-step mechanism where an organolithium base coordinates to the heteroatom of the directing group prior to the deprotonation step. These experiments underscore the inability of this method to quantify large isotope effects and the need to access the error of the measurements when comparing intra- and intermolecular kinetic isotope effects.

Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic and Chemistry, Pharmaceutical

A series of hydroxylated 2,3-diarylindenes were prepared and evaluated as fluorescent ligands for the estrogen receptor. A practical fluorescent estrogen would allow cell-by-cell quantitation of the estrogen receptor in breast tumors, providing a prognostic tool for the clinical differentiation of hormone-responsive and unresponsive tumors. The 2,3-diarylindenes and -indenones were inefficient as photofluorogenic estrogens due to geometric considerations and competition from fluorescence and intersystem crossing. Crystallography indicated more planar topography for the indenes and indenones as compared to other triarylethylenes. The estrogen receptor binding affinities of the indenes, indenones, and other triarylethylenes were related to the torsional and valence angles at the double bond. The intrinsic fluorescence of the 2,3-diarylindenes was found at too short of a wavelength (420 nm) to be useful in biological studies. However, a long emission wavelength and high environmental sensitivity was attained by affixing an acceptor nitro auxochrome to the 2-aryl ring. In the p-position, the nitro group produced a quasi-planar intramolecular charge transfer state, with emission from 490 nm in heptane to 672 nm in acetonitrile. In the m-position, a nitro group produces a twisted intramolecular charge transfer (TICT) state with emission up to 690 nm in chloroform. A nitro group in the m-position or a nitro, bromo, or cyano group in the p-position of the 2-ring all greatly reduce estrogen receptor binding affinity. A hydroxy group in the p-position of the 2-ring enhances binding affinity. Methylation of C-1 produces a modest enhancement in binding affinity. Ortho-substitution of the 2-ring by methyl or trifluoromethyl groups produces significant increase in the estrogen receptor binding affinity. Recommendations for the future development of fluorescent estrogens are made.

Chemistry, Organic

To this end, naphthoyl substituted cytosines were synthesized and incorporated into PNA monomers followed by preparation of PNA oligomers containing multiple substitutions of the modified cytosine. Thermal denaturation studies and thermodynamic analyses of resulting PNA·DNA duplexes were performed to determine the stabilization due to added stacking between the naphthoyl substituents aligned within the major groove. PNA·DNA duplex stabilization was observed when three naphthoyl substitutions were aligned when compared to the same PNA·DNA duplex with separated naphthoyl substituents; however, an overall destabilization was observed when compared to the unsubstituted PNA·DNA duplex. Future modifications are considered to enhance the overall stability of PNA·DNA duplexes containing modified nucleosides.

Chemistry, Organic

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Chemistry, Organic

A diastereoselective [4+2] annulation of vinyl carbodiimides with chiral N-alkyl imines has been developed to access the stereochemically rich anti-fused polycyclic guanidine cores of the batzelladine alkaloids. Application of this strategy, together with additional key steps such as a long-range directed hydrogenation and a diastereoselective intramolecular iodoamination, led to highly convergent total syntheses of (-)-batzelladine D and (+)-batzelladine A with excellent stereocontrol. Overall, a 13 step asymmetric synthesis of -(-)batzelladine D was accomplished in 7.4% yield, and a 20 step asymmetric synthesis of (+)-batzelladine A was completed in 2.0% yield. Investigations into the application of the imine/vinyl carbodiimide [4+2]-annulation to the syn-fused tricyclic guanidine cores of the batzelladines are also described.

Chemistry, Organic

Oxazoline N-oxides have been prepared in medium to high yields under mild conditions by condensation of 2-(hydroxyamino)-2-methyl-1-propanol with ortho esters or amide acetals. 3 + 2 Cycloaddition reactions of the oxazoline N-oxides and the related pyrroline N-oxides with phenyl isocyanate, dimethyl acetylenedicarboxylate, methyl phenylpropiolate, phenylpropiolonitrile, methyl acrylate, and acrylonitrile were carried out. The reaction of 4,4-dimethyl-2-phenyloxazoline N-oxide with acetylenic dipolarophiles in concentrated solutions of dimethylamine hydrochloride in dichloromethane, however, led to the formation of isoxazoles. Competitive experiments demonstrated that 2,4,4-trimethyloxazoline N-oxide is at least 6,800 times more reactive toward phenyl isocyanate than the analogous 2,5,5-trimethylpyrroline N-oxide, and is 160 times more reactive toward dimethyl acetylenedicarboxylate than the pyrroline N-oxide. Rate constants for the 3 + 2 cycloaddition reactions of 4,4-dimethyl-2-phenyloxazoline N-oxide and 5,5-dimethyl-2-phenylpyrroline N-oxide with phenyl isocyanate and dimethyl acetylenedicarboxylate were measured. These data indicate that the oxazoline N-oxide is approximately 76,000 times more reactive toward phenyl isocyanate than the pyrroline N-oxide, and is 70 times more reactive toward dimethyl acetylenedicarboxylate than the pyrroline N-oxide. An explanation for the enhanced reactivity of oxazoline N-oxides is forwarded on the basis of frontier molecular orbital theory.

Chemistry, Organic

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Chemistry, Organic

We have examined the chemical and physical properties of two acylnitrenes, 4-acetylphenoxycarbonylnitrene (APN) and $\beta$-naphthoylnitrene (BNN) generated by the photolysis of 4-acetylphenoxycarbonyl azide and $\beta$-naphthoyl azide (BNA) respectively. These nitrenes were investigated using low-temperature optical, electron spin resonance, and transient absorption spectroscopy as well as by traditional chemical trapping techniques.

Chemistry, Organic

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Chemistry, Biochemistry, Chemistry, Organic, and Chemistry, Pharmaceutical

The corresponding protio enol lactones showed only transient inhibition (not inactivation) due to the lack of halogen in the lactone molecule, but deacylation rates of 4-phenyl-6-methylenetetrahydro-2-pyranone ($\beta$Ph6H) and 3-(1-naphthyl)-6-methylenetetrahydro-2-pyranone ($\alpha$Np6H) were very slow, and they are thus still effective inhibitors by formation of stable acyl enzymes. In order to understand this slow deacylation and stereospecific behavior of inhibition, protio enol lactones were resolved into their two enantiomers, and the effects of the structure variation of the lactones on the inhibition kinetics were studied. This study shows that S enantiomer binds more strongly to the active site of the enzyme than R enantiomer, and the deacylation rates of the R enantiomers of $\beta$Ph6H and $\alpha$Np6H are very slow, with the half-lives of 4.0 h and 12.6 h at pH 7.2, respectively. The enantioselectivity of deacylation of these lactones is very large, with the R enantiomers having 60-70 fold slower deacylation rates than the S enantiomers. This slow deacylation could be explained by a twisted acyl enzyme model. Since deacylation is the rate-determining step, these lactones with very slow deacylation rates act as alternate substrate inhibitors.

Chemistry, Organic

The fully functionalized nitroalkene intermediate for the total synthesis of daphnilactone has also been prepared and participated in the high yielding tandem double-intramolecular [4+2]/[3+2] cycloaddition to provide a mixture of two epimeric nitroso acetals. Ozonolysis of the cycloadducts, followed by hydrogenolysis and intramolecular acylation provided the intermediates for the total synthesis that may be elaborated to daphnilactone B. Possible routes to complete the synthesis are also discussed.

Chemistry, Organic

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Chemistry, Organic

A procedure for the preparation of multi-substituted indoles using the Larock indole synthesis was developed. The heteroannulation reaction can be used to prepare 2,3-disubstituted indoles in good yields. The identification of a t-butoxysilyl ether as the masked silanol further expanded the scope of this reaction.

Chemistry, Organic

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Chemistry, Organic

Semiempirical molecular orbital calculations based on a MINDO/3 program were performed on 5-methyl-5H-adenine and its proposed intermediacy in a translocative rearrangement. The results revealed the relative instability of 5-methyladenine with respect to the stability of the final rearrangement product 4-amino-8-methylimidazo{1,5-a}triazine. The calculations also provided insight into the probable loci of bond-breaking and into the structures of the potential intermediates in the ring opening of 5-methyladenine.

Chemistry, Organic

These triazaadamantane macromolecules may find broad application as drug carriers and for the encapsulation and release of other substances, similar to the Trojan horse strategy. Their ability to act as proton sponges makes them particularly interesting with regards to their potential as artificial gene delivery vectors.

Chemistry, Organic

Part I. Three molecular tweezers have been synthesized to determine the role of preorganization in the host-guest complexation of these systems. The synthesis of these tweezers was accomplished by the reaction of their respective dibromo-pyrylium salts with an absolute ethanol/aqueous ammonium hydroxide solution followed by a lithium/halogen exchange and addition of dimethoxyacridone chromophores. Tweezers 11-13 have zero, one, and two additional degrees of free rotation, respectively, which lessens the enforced syn cofacial orientation of the diacridine chromophores and the overall rigidity of the system. $\sp1$H NMR binding studies indicate an increase in the association constant (K$\sb{a}$) with the increase in rigidity. The effects of increasing rigidity are additive with $\rm\Delta\Delta G\sp\circ\sb{13\to11}=2\Delta\Delta G\sp\circ\sb{13\to12}$ = 1.8 kcal$\cdot$mol$\sp{-1}$. Thus, the enforced syn orientation of 11 provides no special benefit other than its role in preorganizing the host.

Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

Lithiation of oxy-arenes was studied. The lithiation of 4-hydroxyphenanthrene with 2 eq. of n-butyllithium/TMEDA in cyclohexane at 23(DEGREES)C occurs completely at the 5-position, although the 5-position is the most hindered position in the 4-hydroxyphenanthrene. By contrast, the lithiation of 4-methoxyphenanthrene by 1 eq. of n-BuLi/TMEDA in cyclohexane at 23(DEGREES)C occurs exclusively at the 3 position. Similarly, lithiation of (alpha)-naphthol under the same reaction condition gave 8-position lithiation and 2-hydroxybiphenyl was lithiated at the 2'-position. New reagents, 1,2-dibromo- and 1,2-dichloro-tetrafluoroethane were used for the halogenation of the lithiated positions. These remote lithiation reactions are useful in the synthesis of theoretically interesting heterocyclic heptalene and pyrene systems.

Chemistry, Organic

The use of substoichiometric amounts of TMSCl as an electrophile is found to provide the product with higher enantiomeric excess than when excess TMSCl is used. This is suggested to arise as a consequence of kinetic resolution of non-equilibrating diastereomeric ligand/organolithium complexes. We have utilized this observation to amplify the enantioselectivity of the reaction sequence by using the electrophile as the limiting reagent and recycling the unwanted diastereomeric complex. An energy diagram for the reactions of the diastereomeric complexes is presented, and the stereoinformation transfer is suggested to occur via a dynamic thermodynamic resolution.

Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

In an investigation of the formation of dipole-stabilized carbanions from thioesters, deprotonation of a tertiary center at the carbon adjacent to the sulfur of a thioester was found for the first time. Isopropyl, 2-octyl, and 4-tert-butylcyclohexyl 2,4,6-triisopropylthiobenzoates react with sec-butyllithium/TMEDA at -98(DEGREES)C to give synthetically useful (alpha)-lithio thioesters. These species react with electrophiles including primary alkyl halides and a variety of carbonyl compounds to give substituted thioesters. Study of the optically active 2-octyl thioester as well as the cis-4-tert-butylcyclohexyl thioester has shown that (alpha)-lithio thioesters are not configurationally stable. A general synthesis of trisubstituted thiiranes is provided by the action of sodium hydride on (beta)-hydroxy thioesters, which are obtained by reaction of the (alpha)-lithio thioesters with aldehydes.

Chemistry, Organic

Part B. Progress towards a new family of hyperbranched polymers based on the condensation of an AB$\sb2$ 9-phenylcarbazole monomer 169 has been described. Initial condensation reactions have provided material of greater than 100,000 mw as determined by GPC. No estimate of the degree of branching has been made. Evidence for olefinic linkages between carbazole units is provided by an observed red shifting in the absorption spectrum and chemical derivatization with bromine in carbon tetrachloride. These initial observations suggest that an in depth characterization of hyperbranched products from this family of compounds is warranted.

Chemistry, Organic

Dendrimers having 16, 24, 32, or 64 alkene groups were synthesized and intramolecularly cross-linked. The combined use of MALDI-TOF MS and SEC analysis of the resulting structures indicated that in each case, as the degree of dendrimer cross-linking increased, its radius of gyration (Rg) decreased linearly. Upon cross-linking of the dendrimer having 64 alkene groups, atomic force microscopy (AFM) data indicated that as the degree of cross-linking increased, the height of the resulting structure deposited on a mica surface increased linearly. These results were interpreted in terms of an increase in rigidity with cross-linking. In addition, smaller dendrons and a dendrimer having 16 alkene groups were cross-linked, and the resulting structures were analyzed by 1H NMR, x-ray crystallography, MALDI-TOF MS, and SEC to provide insight into the types of the cross-links that are preferred in the cross-linking process.

Chemistry, Organic

The differential deacylation rates for alpha-chymotrypsin beta-phenyl acyl enzymes 13 and 14 have been studied using the techniques of molecular mechanics and molecular dynamics. These studies indicate that the ketone side-chain of slowly deacylating acyl enzyme 13 is hydrogen bonded to the NH of Gly-216, and that the force of this hydrogen bond along with other non-bonded interactions pulls the ester carbonyl group out of the oxyanion binding hole. This distortion of geometry raises the energy of activation for hydrolysis of the acyl enzyme by providing little stabilization of the negative charge that develops during the rate determining process of tetrahedral intermediate formation. This is in contrast to the results for the relatively quickly deacylating acyl enzyme 14, which has a ketone carbonyl hydrogen bonded to the Gly-216 NH, and an ester carbonyl that remains hydrogen bonded to both NH's of the oxyanion binding hole. Additional evidence for the differential kinetics observed is provided by molecular mechanics and molecular dynamics studies of the deacylation tetrahedral intermediates formed by acyl enzymes 13 and 14. It is shown that whereas the tetrahedral intermediate formed from slowly deacylating acyl enzyme 13 has an oxyanion hydrogen bonded ideally to only the Ser-195 NH, the oxyanion formed from 14 has good hydrogen bonds to both the Gly-193 and the Ser-195 NH's.

Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

The estrogen receptor (ER) has become a major focus of biological and clinical investigation in diagnostic and therapeutic drug design for human breast carcinoma. Molecular probes, such as fluorine-18 radiopharmaceuticals, bivalent ligands, and affinity labels, provide information toward a better understanding of ER localization, structure, and function. We have prepared two fluorinated analogs of 2-oxohexestrol as potential diagnostic imaging agents for ER-responsive human breast tumors. These ligands were prepared in fluorine-18 labeled form with high specific activity (328-609 Ci/mmol) by fluoride ion (n-Bu$\sb4$N$\sp{18}$F) displacement of a mesylate and triflate precursor. Preliminary studies on the unlabeled compounds showed them to have low lipophilicity and good receptor binding affinity; these results were reflected in the tissue distribution studies of the radiolabeled compounds with moderate selective uptake in target tissues (uterus, ovaries) and substantial receptor-mediated uptake in secondary tissues (thymus, muscle, kidney, fat).

Chemistry, Organic

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Chemistry, Organic

The concept of Lewis base activation of Lewis acids has been effectively reduced to practice for catalysis in the chiral phosphoramide catalyzed/SiCl 4 promoted aldol reaction of silyl ketene acetals and silyl dienol ethers with aldehydes. The weakly acidic species, silicon tetrachloride (SiCl 4), is activated by binding of a strongly Lewis basic chiral phosphoramide, leading to in situ formation of a chiral silyl cation. This species has proven a competent catalyst for the aldol addition of acetate-, propanoate- and isobutyrate-derived silyl ketene acetals to conjugated and non-conjugated aldehydes. Furthermore, vinylogous aldol reactions of silyl dienol ethers are also demonstrated. The high levels of regio-, anti diastereo- and enantioselectivity observed in these reactions can be rationalized through consideration of an open transition structure where steric interactions between the silyl cation complex and the approaching nucleophile are dominant. Kinetic studies undertaken using ReactIR spectroscopy show that the reaction displays saturation kinetics in SiCl4. This suggests that the phosphoramide bound silyl cation complex is the catalyst resting state. Spectroscopic studies have garnered support for this conclusion through the observation of the phosphoramide bound silyl cation complex by 29Si NMR.

Chemistry, Biochemistry and Chemistry, Organic

Tunichlorin, a nickel chlorin isolated from the Caribbean tunicate Trididemnum solidum, has been identified as nickel (II) 2-devinyl-2-hydroxymethylpyropheophorbide a by chemical and spectroscopic methods. A partial synthesis of dimethyl tunichlorin from chlorophyll a (7 steps, 5% overall yield) has also confirmed the proposed structure. In the living tunicate, tunichlorin appears to exist primarily as a series of C-14 to C-18 ester homologues (principally tunichlorin-COO-(C$\sb3$H$\sb4$O)-(CH$\sb2$)$\sb{14}$CH$\sb3$). Preliminary studies suggest that tunichlorin esters are biosynthesized by the tunicate from alga-produced chlorophyll a. Although the biological function of tunichlorin esters remains unclear, analogy to related compounds suggests that they may be enzyme cofactors involved in reductive processes.

Chemistry, Inorganic and Chemistry, Organic

Transition metal-cysteine complexes are reviewed in Chapter 1. Compounds for which X-ray crystal structures have been determined are considered first followed by those for which only spectroscopic evidence exists. The synthesis and characterization of several trans-dioxoruthenium(VI) species containing cysteine(2$-)$ and related ligands is reported in Chapter 2. The compounds $\rm Ru(O)\sb2(py)\sb2(SC\sb2H\sb5)\sb2,$ Ru(O)$\sb2$(py)$\sb2\{$SCH$\sb2$CH$\sb2$C(O)O$\},$ Ru(O)$\sb2$(bpy)$\{$SCH$\sb2$CH(NCHO)C(O)O$\},$ Ru(O)$\sb2$(py)$\{$SCH$\sb2$CH(NHCOMe)C(O)O$\},$ and Ru(O)$\sb2$(bpy)$\{$SCH$\sb2$CH(NHCOMe)C(O)O$\}$ have been synthesized in yields ranging from 60-87% from Ru(O)$\sb2$(OH)$\sb2$(py)$\sb2$ and Ru(O)$\sb2$Cl$\sb2$(bpy) using either ethane thiol, 3-mercaptopropionic acid, N-acetyl-L-cysteine, or N-formyl-L-cysteine. The iron(II) and iron(III) complexes (NBu$\sb4\rbrack\sb{\rm n}$ (Fe(SCH$\sb2$CH(NHCOCH$\sb3)$COO)$\sb2$) (n = 1,2) have been synthesized by the addition of two equivalents of N-aceteyl-L-cysteine to methylene chloride solutions of either (NBu$\sb4$) (Fe$\sp{\rm III}$(OSiMe$\sb3)\sb4$) or (NBu$\sb4\rbrack\sb2$(Fe$\sp{\rm II}$(OSiMe$\sb3)\sb4$) and are described in Chapter 3. The synthesis and characterization of the first monooxo ruthenium(VI) tetraalkyl complex, (Ru(O)(CH$\sb2$Si(CH$\sb3)\sb3)\sb4$), is reported in Chapter 4 along with that for Ru(CH$\sb2$Si(CH$\sb3)\sb3)\sb4.$ These complexes are readily synthesized from trans-(PPN) $\sb2$(Ru(O)$\sb2$Cl$\sb4$) and either four or ten equivalents of trimethylsilyl-methylmagnesium chloride in THF or methylene chloride respectively. In Chapter 5, combination of (C$\sb5$H$\sb9)\sb7$Si$\sb7$O$\sb{12}$H$\sb3$ with either (NBu$\sb4$) (Fe(OSiMe$\sb3)\sb4$) or (NBu$\sb4$) (Fe(Cl)$\sb4$) and triethylamine gives the iron-containing silsesquioxanes (NBu$\sb4$) ((C$\sb5$H$\sb9)\sb7$Si$\sb7$O$\sb{12}$FeCl) and (NBu$\sb4$) ((C$\sb5$H$\sb9)\sb7$Si$\sb7$O$\sb{12}$FeOSi(CH$\sb3)\sb3$) in yields of at least 60% after recrystallization from toluene/hexane. These complexes can be modified by substitution for the free siloxide or chloride ligand to give (NBu$\sb4$) ($\{$(C$\sb5$H$\sb9)\sb7$Si$\sb7$O$\sb{12}$Fe$\}\sb2$O), (NBu$\sb4$) ((C$\sb5$H$\sb9)\sb7$Si$\sb7$O$\sb{12}$FeOOC(CH$\sb3)\sb3$), and (NBu$\sb4$) ((C$\sb5$H$\sb9)\sb7$Si$\sb7$O$\sb{12}$Fe(S-cysteine-OMe)).

Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

Cyclodextrins (CDs) are amphiphilic carbohydrate based macrocycles that have been under-utilized in supramolecular chemistry due to difficulties surrounding the selective functionalization of the hydroxyl groups on the macrocycle. A novel strategy for the synthesis of CD analogues is described which involves the use of [3+2] Huisgen cycloadditions between azide and alkyne functionalities to form the macrocycles from linear precursors. This strategy is used in the synthesis of a trisaccharide cyclodimer which was shown to complex a fluorescent dye 8-anilino-1-naphthalene sulfonate with an association constant of 38 +/- 10 M-1. In addition, the synthesis of a monosaccharide cyclotrimer and a disaccharide cyclodimer is presented that were demonstrated to complex 2,4-hexadiyne-1,6-diol with association constants of 8.8 +/- 1.5 M -1 and 10.4 +/- 1.1 M-1, respectively. Alternate synthetic routes which incorporate selectively installed orthogonal protecting groups are discussed for each of the three types of CD analogues. Efforts toward the synthesis of a gated molecular pore are also detailed.

Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

A structure-activity study was done on a series of 6-halo-2-pyranones as suicide inhibitors of chymotrypsin. In the 6-chloro-2-pyranone series, substitution in the 3- position of the pyrone by either ethyl or n-butyl produced poor binding relative to 3-benzyl-6-chloro-2-pyranone, and no inactivation. Increasing the aromatic area of the binding group by replacing the benzyl group with a naphthylmethyl had a dramatically different effect, depending upon the naphthyl substitution; 3-(2-naphthyl)methyl-6-chloro-2-pyranone inhibited chymotrypsin 33-fold faster than the benzyl pyrone and 100-fold faster than the 1-naphthyl isomer. Models suggest that this great difference is a consequence of binding, not steric inhibition.

Chemistry, General, Chemistry, Analytical, and Chemistry, Organic

Systematic investigations of chiral recognition mechanisms have led to chiral selectors which, when immobilized and used as chromatographic stationary phases, show high levels of enantioselectivity. Since these selectors are designed to function in essentially the same manner whether immobilized or in solution, the chromatographic data enable one to quickly evaluate the suitability of a selector for use in hollow-fiber membrane systems. Several chromatographically developed selectors show promise for large scale separation of enantiomers using hollow-fiber membrane technology. Chiral selectors derived from N-(1-naphthyl)leucine have been used in a hollow-fiber membrane system (Sepracor) to separate the enantiomers of amino acid derivatives. Enantiomeric purities exceeding 95% have been obtained in a single pass through the system. For data collection, sample sizes were limited to gram quantities of racemate. However, it is clear that the present system could be used to resolve larger samples and that the continuous (as opposed to batch) process scale separation of enantiomers is feasible by this approach.

Chemistry, Organic

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Chemistry, Organic

While several promising inhibitors of PARP have been developed, no crystal structure of the complementary enzyme poly(ADP-ribose)glycohydrolase (PARG) is available, and therefore it has been difficult to intelligently design compounds to inhibit this enzyme. To date, the known inhibitors of PARG can be predominantly grouped into the three categories of DNA intercalators, tannins, and ADP-ribose analogues. While these compounds have proven valuable in the in vitro analysis of PARG, due to toxicity (intercalators), cell permeability issues (ADP-HPD), and nonspecific activity (tannins), few if any of these compounds have been useful for evaluating the effects of PARG inhibition in cell culture and in vivo. Thus, efforts to synthesize and assess cell ADP-HPD based PARG inhibitors will be discussed in the second half of this document. Furthermore, as compounds based on rhodanine scaffolds have been identified as inhibitors of enzymes utilizing pyrophosphate-containing substrates, we have screened a collection of rhodanine-containing small molecules for their ability to inhibit PARG. Through this screen several novel PARG inhibitors were identified, and subsequent derivative synthesis has elucidated structural features important for PARG inhibition. Several of the compounds are cell permeable and induce the build-up of poly(ADP-ribose) in the cell. Details of the TLC based screen, synthesis, and evaluation of hit compounds in cell culture will be discussed.

Chemistry, Organic

In studies directed towards the development of radiolabelled probes for progesterone receptor in mammary tumors and androgen receptor in prostate tumors, a series of fluorinated progestins and androgens were prepared. Fluoride was introduced into the 6(alpha)-, 11(beta)- and 16(alpha)-positions of the molecules by bromofluorination of an appropriate alkene, and into the 17(alpha)-position by substitution of a methansulfonate using tetrabutylammonium fluoride or fluoride ion cleavage of a spiro epoxide or cyclic sulfate. The affinities of the compounds for progesterone- and androgen receptors were determined, and several of the steroids were found to exhibit the good affinities and selectivities for their respective receptors predicted on the basis of general substituent trends. Fluoropropynyl nortestosterone 119 bound with the highest affinity to progesterone receptor (66% that of progesterone), and 11(beta)-fluoro-19-nordihydrotestosterone (90) maintained the highest affinity for androgen receptor (130% that of dihydrotestosterone) of the compounds tested. Nortestosterone 119 can be rapidly prepared in good yield by the fluoride displacement of the corresponding methanesulfonate 131. Similarly, the synthesis of fluorodihydrotestosterone 76, a model for nordihydrotestosterone 90, was modified in order that fluoride can be introduced quickly and efficiently. The two-step reaction sequence involves a bromofluorination followed by reductive debromination.

Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

Mechanistic investigations of several chiral stationary phases (CSPs) were undertaken. These investigations were carried out in an effort to understand the recognition processes responsible for the observed enantioselectivities on the CSPs of interest. Several spectroscopic and chromatographic approaches were taken to establish working models for the recognition processes involved. Specifically, the spectroscopic ($\sp1$H-NMR) studies focused on the solution state behaviors of several CSP analogs in the presence of the individual enantiomers of suitable analytes. Based on observed chemical shift changes and intra- and intermolecular nuclear Overhauser effects upon complexation, conclusions were made with regard to the validity of the initially proposed chiral recognition mechanisms. The chromatographic studies were derived from a basic understanding of these recognition mechanisms. In one case, the role of CSP rigidity is probed and in another, the importance of selector orientation with respect to the underlying silica support is investigated.

Chemistry, Organic

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Chemistry, Organic

The use of the diethyl and diisopropyl amide functions as acid oxidation level directing groups was explored. Addition of N,N-diethylbenzamide to s-BuLi-TMEDA at -78(DEGREES) in THF solution results in rapid formation of the o-lithio species. The anion was treated with D(,2)O, alkyl iodides, carbonyl compounds, ClSiMe(,3) and B(OMe)(,3) followed by H(,2)O(,2) to give the ortho substituted products in yields of 52-84%. Similarly, N-N-diisopropylbenzamide was treated with s- or n-BuLi-TMEDA followed by D(,2)O, MeOD, allyl bromide or CO(,2) to give ortho substituted products in yields of 21-87%. A mechanistic study indicated lithiation of the ortho position is direct rather than the result of rearrangement of an initially formed (alpha)-aza anion.

Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

Chiral phosphoramide-catalyzed, enantioselective aldol additions of isobutyraldehyde-derived trichlorosilyl enol ether to aldehydes have been investigated. These aldol additions are general and provide beta-hydroxy aldehydes protected as dimethyl acetals in high yields albeit moderate selectivities. Enantioselectivities are highly dependent on the electronic nature of aldehyde substituent. Two linear but divergent trends in selectivity observed for electron-rich and electron-poor aromatic aldehydes exist. Studies of Arrhenius activation parameters and 12C/13C kinetic isotope effects at natural abundance indicated that no significant change in mechanism occurs up on changing the electronic nature of aldehydes. The divergent trends in selectivity were interpreted according to the Hammond postulate and the Curtin-Hammett principle. Also, chiral phosphoramide-catalyzed, enantioselective Mukaiyama-type aldol reactions of acetaldehyde with other aldehydes have been achieved. Aldol products from aromatic aldehydes were obtained in high yields and selectivities. Intermediates in these aldol additions have been spectroscopically identified as chlorohydrins, and they can be trapped in situ with tert-butyl isocyanide to afford an alpha-hydroxy lactone and alpha-hydroxy amide in good overall yield. Last, proof of principle for Lewis base activation of acids in reactions of silyl ynol ethers with aldehydes has successfully demonstrated. Particularly, the phosphoramide/SiCl4 system has been shown to function as a catalyst in these reactions. More importantly, experimental results have revealed that a new stereogenic center can be created and preserved in these processes.

Chemistry, Organic

Our developments toward the total synthesis of the original and revised structures of palau'amine are presented in this study. This includes the construction of the fully functionalized cyclopentane cores of both the original and revised structures via the application of a Diels-Alder/[3,3]-sigmatropic rearrangement of tricyclodecadienes. A cyclization strategy for the formation of the strained trans-fused azabicyclo[3.3.0]octane bicyclic system of the core of the revised structure of palau'amine was also developed within the context the natural product analogs dimethylcyclopentaphakellin and 10,6-epidimethylcyclopentaphakellin utilizing an intramolecular azide [3+2]-dipolar cycloaddition. Also of note is the development of new methods for the preparation of the polycyclic pyrazinones. Application of this cyclization strategy has allowed for synthesis of the advanced intermediates possessing the fully functionalized skeleton of the revised structure of palau'amine encompassing the A, E, and D rings.

Chemistry, Organic

Treatment of N,N -diisopropyl-3-benzenesulfonyl-2-methylenepropanamide with lithium 2,2,6,6-tetramethylpiperidide in tetrahydrofuran at $-$78$\sp\circ$C produces the stable N,N-diisopropyl- ((1-benzenesulfonyl)-2-carbamoylallyl) lithium reagent which when allowed to react with electron-deficient olefins produces 4-substituted-N,N-diisopropylcyclopent-1-ene carboxamides in 89% to 22% yields. Similarly, allyllithium reagents have also been formed from the less hindered tertiary amide, N,N-dimethyl-3-benzenesulfonyl-2-methylenepropanamide, and the secondary amide, N-phenyl-3-benzenesulfonyl-2-methylenepropanamide, and then allowed to react with cyclohexyl methacrylate to produce the N,N-dimethyl- and N-phenyl-4-cyclohexyloxycarbonyl-4-methylcyclopent-1-ene carboxamides in 49% and 19% yields respectively. Acid hydrolysis of these two cyclopentenes produces 4-methylcyclopent-1-ene-1,4-dicarboxylic acid in 62% and 77% yields respectively. Studies with allyllithium reagents derived from N,N-diisopropyl-3-benzenesulfonyl-2-methylenebutanamide and N,N-diisopropyl-2-(benzenesulfonylmethyl)but-2-enamide show that alkyl substitution on either end of the allyllithium reagent can be tolerated and cyclopentenes are produced even though decreased yields are obtained. This allows for the synthesis of cyclopentene products which are substituted in the two or five positions.

Chemistry, Organic

The 1-aza-1'-oxa-{3,3}-sigmatropic rearrangement of N-aryl-O-vinyl-hydroxylamine derivatives has been investigated as a synthetic method for the ortho alkylation of benzene rings. The general approach involved the in situ formation of N-aryl-O-vinylhydroxamates which rearranged under the conditions required for their synthesis. The O-vinylation of N-aryl-hydroxamic acids was accomplished by Michael-type addition of the hydroxamic acids to acetylenic esters, (beta)-chloroacrylates, and (alpha)-allenic esters. The requirements and limitations for the 1,4-addition reaction have been defined. The products obtained from these reactions are substituted anilides which bear (beta)-oxo-alkyl groups ortho to the acetylamino group. The reaction of N-arylacetohydroxamic acids with methyl propiolate or methyl (beta)-chloroacrylate gave 2-(acetylamino)-(alpha)-formylbenzeneacetates. The {3,3}-sigmatropic rearrangement of the O-vinylhydroxamates prepared from the 1,4-addition of N-arylhydroxamic acid to (alpha)-allenic esters occurred entirely with the double bond of the vinyl group in the (beta),(gamma)-position, affording 2-(acetylamino)-(beta)-oxobenzene butanoates in 34-79% yields.

Chemistry, Organic and Chemistry, Pharmaceutical

The use of chiral stationary phases (CSPs) for the separation of enantiomers is commonplace. A variety of $\alpha$-alkyl and $\alpha$-aryl substituted $\alpha$-amino phosphonates were prepared. The ability of several CSPs to separate the enantiomers of N-(3,5-dinitrobenzoyl) derivatives of $\alpha$-alkyl and $\alpha$-aryl substituted $\alpha$-amino phosphonates was investigated. Using the chromatographic structure-activity relationships, chiral recognition models were proposed. For one class of CSP, the chiral recognition model has been further supported using spectroscopic and chromatographic evidence. Two $\alpha$-amino phosphonate derived CSPs were prepared and their ability to separate the enantiomers of a variety of analytes was studied. The mechanistic implications of analyte-CSP spatial complementarity were investigated. Two new CSPs derived from the 3,5-dinitrobenzamide of an $\alpha$-amino acid were prepared and evaluated.

Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

Two unsymmetrical, differentially substituted 1,2-bissilylethylene reagents were prepared and subsequently examined in sequential cross-coupling reactions. These reagents successfully react in the first coupling with aryl iodides and an electron-deficient alkenyl iodide under "fluoride-free" conditions. The second, fluoride-activated cross-coupling was explored.

Chemistry, Organic

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Chemistry, Organic

Ab initio SCF calculations on the hypothetical complexes ((eta)('3)-C(,3)R(,3))(,2)E (R = H, E = Si, S) indicate that closed shell electronic configurations may exist for either 8, 10 or 12 electron species. The synthesis of such species (for R = CF(,3) and E = nonmetal) has so far been unsuccessful. The effects of placing electron withdrawing substituents on ((eta)('3)-C(,3)R(,3))-transition metal complexes has also been evaluated. The synthesis and X-ray structure determination of ((eta)('5)-C(,5)H(,4)CH(,3)) (eta)('3)-C(,3)(CF(,3))(,3) Mo(CO)(,2) (1), the first (eta)('3)-C(,3)R(,3) complex that incorporates an electron withdrawing C(,3)(CF(,3))(,3) ring, is best described not as a (eta)('3)-cyclopropenium complex but as a metallatetrahedrane.

Chemistry, Organic

Part One. The Diels-Alder reactions of electron-rich alkenes and alkadienes in a photochemical electron transfer system are presented. In acetonitrile, the Diels-Alder dimerization of 1,3-cyclohexadiene (1) is shown to be the result of the reaction of the radical cation of 1. A chain mechanism and a fast rate constant for addition of the radical cation of 1 to a neutral molecule of 1 are applied to explain a similar reaction using an aminium salt catalyst. In benzene, the Diels-Alder adducts are produced via a triplex intermediate. Product and spectroscopic studies for five triplex reactions are presented. Some preliminary observations about this reaction also are discussed.

Chemistry, Organic

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Chemistry, Organic and Agriculture, Fisheries and Aquaculture

The biosynthesis of brominated tyrosine metabolites by the marine sponge Aplysina fistularis was investigated. ($U$-$\sp{14}$C) -L-Tyrosine, ($U$-$\sp{14}$C) -L-3-bromotyrosine, and ($U$-$\sp{14}$) -3,5-dibromotyrosine were incorporated into both dibromoverongiaquinol and aeroplysinin-1, and (methyl-$\sp{14}$C) methionine was specifically incorporated into the O-methyl group of aeroplysinin-1. (Methyl-$\sp{14}$C) -O-methyltyrosine and (methyl-$\sp{14}$C) -3,5-dibromo-O-methyltyrosine and several putative nitrile precursors were not significantly incorporated into aeroplysinin-1.

Chemistry, Organic

Efforts to prepare the stemofoline alkaloids via total synthesis are described. Each strategy which is presented utilized a [3+2] cycloaddition of a non-stabilized azomethine ylide as a key step. These studies culminated in the first non-racemic synthesis of the fully-oxygenated tricyclic core of the stemofoline alkaloids. Furthermore, a novel synthetic method to prepare alpha-linked C2-acetamido glycoconjugates is described and preliminary results are presented.

Chemistry, Organic

The ethyl, n-propyl, n-octyl, n-hexadecyl, n-benzyl and 2'-(N,N-dimethylamino)ethyl 2,4,6-triisopropylbenzoates afforded stable (alpha)-oxocarbanions upon treatment with sec-butyllithium-tetramethylethylenediamine at -78(DEGREES)C. Allyl and 2'-methoxyethyl 2,4,6-triisopropylbenzoate underwent successful (alpha)-oxometalation but did not afford stable (alpha)-oxocarbanions. Successful metalations under these conditions were also performed on methyl, ethyl and n-pentyl 2,6-bis(dimethylamino)-3,5-diisopropylbenzoate. Electrophiles successfully employed in this synthetic sequence include deuteriomethanol, methyl iodide, 1-iodobutane, 1-iodopentane, allyl bromide, chlorotrimethylsilane, chlorotri(n-butyl)tin, N,N-dimethylmethyleneammonium iodide, acetaldehyde, cyclohexanone, acetone, and 2-cyclohexen-1-one. The isopropyl esters of 2,4,6-triisopropylbenzoate and 2,6-bis(dimethylamino)-3,5-diisopropylbenzoate could not be metalated under a wide variety of conditions.

Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

Carboxylation of endocyclic enolate anions with methyl cyanoformate and carbon dioxide proceeds in fair to good yields (25 to 76%). When methyl cyanoformate is used, the enol carbonate is a major side product (8 to 34%) with six-membered ring enolates, and enolate hydrolysis ketone is the major side product (11 to 22%) when carbon dioxide is used. In general, both the methyl cyanoformate and carbon dioxide approach trans to the other substituent on the enolate ring. Although the stereoselectivity of C-carboxylation of six-membered ring enolates is greater with methyl cyanoformate than with carbon dioxide, the actual isolated yields of the major $\beta$-keto esters are similar owning to the formation of substantial amounts enol carbonates with the former reagent. The stereoselectivity for the two reagents is about equal for five- or seven-membered ring enolates and is usually $\geq$93:7 with Mander's reagent. The stereochemistry of the methyl cyanoformate carboxylations is rationalized by a stereoelectronic effect and a late transition state while carbon dioxide carboxylation is proposed to proceed through an earlier and less sterically demanding transition state. The carboxylation reaction with both reagents appears to be irreversible and product stability seems to be unimportant. The carboxylation stereoselectivity of the enolate of 2,6- dimethylcyclohexanone with carbon dioxide is anomalous, attack occurring predominantly cis to the C-6 methyl group. Steric interactions between the tetracoordinated lithium ion and the C-6 methyl group together with an anti S$\sb{\rm E}\sb{\sp\prime}$ mechanism are involked to rationalize the stereoselectivity in this case.

Chemistry, Organic

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Chemistry, Organic

The diastereoselectivity of organometallic additions to nitrones bearing stereogenic substituents has been investigated. High and complementary diastereoselectivity was observed in the additions of Grignard reagents to nitrones (e.g. 62) bearing a potentially chelating $\beta$-alkoxy group on nitrogen. The high facial diastereoselectivity is explained by a simple chelation model which was supported(DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI)by $\sp1$H NMR analysis of a nitrone-magnesium bromide complex (86). However, the opposite selectivity resulted from the reaction of methylmagnesium bromide with the corresponding silyl ether (68). N-Deoxygenation of N,N-dialkylhydroxylamine adducts was achieved by lithium-ammonium reduction of the hydroxylamino carbonates (90 and 95) and phosphates (114). N-Dealkylation by periodic acid cleavage of the resulting amino alcohols (91 and 96) and subsequent hydrolysis of the imine products provided non-racemic chiral amines. The optical purities of the amines were determined by HPLC analyses of their 3,5-dinitrobenzamide derivatives (94 and 97). The relative stereochemistry of selected hydroxylamine adducts was established by N-deoxygenation of the adducts to amines (115), by conversion of the adducts to primary amines, by periodate cleavage of a $\beta$-hydroxyhydroxylamine (118) and by various correlations. Low selectivity was observed in the organometallic additions to C-($\alpha$-alkoxy)nitrones (74-76). Organometallic additions to nitrones (70-71) prepared from carbohydrates were also surveyed but further experiments are necessary to explore the potential for chiral amine syntheses by this approach. Formation of tetrahydrooxadiazine dimers in the reactions of N-benzylidene-N-(1-arylalkyl)nitrones with methyllithium was also observed.

Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

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