Background and Purpose

Funded by a $2,500,000 endowment plus a $500,000 Annuity Trust set up with the Southern Illinois University Foundation in March 2,000, the Meyers Institute for Interdisciplinary Research in Organic and Medicinal Chemistry was initiated. The Institute's raison d柳etre is to carry out basic research not restricted to organic chemistry alone but in areas which will also purposely involve the University as a whole, e.g. College of Science, School of Medicine, College of Agricultural Sciences. Basic research leads to new applications, broad-field publications, and patents. Students undertaking research studies in areas associated with the Institute will have the advantage of interacting with students and faculty members in a variety of disciplines, and thus glean a broad experience in fundamental as well as applied scientific research, making them prime candidates for positions in the scientific, medical and commercial sectors. Initially, the Institute is physically situated in the Neckers Building, which houses the Department of Chemistry and Biochemistry.

Additional Funding

The Southern Illinois University Foundation will provide $10,000 annually to the Institute during the tenure of the initial Institute Director. The Foundation will also provide $10,000 annually to the Department of Chemistry and Biochemistry. Grants from agencies such as NSF, NIH, DOD, Research Corporation, etc. are being sought to provide funding for specific projects already underway or being planned. Funding from chemical and pharmaceutical companies, among others, is also being sought, as well as grants and contributions from private individuals.

Functions

Fellowships

The Institute will provide at least two graduate fellowships annually for students carrying out their research in organic chemistry in the Institute. In addition, stipends will be available for postdoctoral and visiting researchers, and summer stipends for undergraduate researchers will be considered.

Symposia

The Institute will sponsor an annual symposium at SIU on a topic of current interest to those carrying out research in the Institute or in an interdisciplinary research area in which the Institute is involved.

Research

The Institute laboratory will house postdoctoral researchers and those on sabbatical leave or leave of absence from academia or industry, and graduate and undergraduate chemistry students, working under the supervision of the Institute's Director or Associate Director along with the Institute柳s collaborators in related departments, colleges and schools in SIU and other universities

Current research areas

(1) Medicinal: Our research team has found that the (+) and (-) enantiomers. respectively, of cis-bisdehyrodoisynolic acid (Z-BDDA) have specific physiological effects in males and females. The (+) enantiomer is very effective in reducing enlarged prostates (BPH) and shows excellent anti-prostate-cancer activity, with very little of the feminizing side effects commonly derived from prostate-cancer therapy. Our studies of the estrogenic carboxylic acids will be continued for the ongoing in vivo and in vitro (cell-line and receptor-binding) investigations being carried out by the Institute柳s physiology collaborators in the School of Medicine and College of Agriculture. Our studies now indicate that the very poor estrogen-receptor (ERa, ERb) binding affinity exhibited by the highly uterotropic estrogenic carboxylic acids, which we reported a few years ago, may be related to the carboxylic acid function, their derivatives, e.g. esters, showing much higher binding affinities. The paradox of why the carboxylic acids are so uterotropically active, therefore, is being investigated. To this end we are preparing possible metabolites of these carboxylic acids, which will be studied for their binding and uterotropic activities. We now have developed a direct asymmetric synthesis of the enantiomeric cis-bisdehydrodoisynolic acids, and the synthesis and biological investigations of the enantiomers of simpler estrogenic non-steroidal carboxylic acids and their esters and lactones is ongoing. Thus, we have found that earlier publications reporting very high uterotropic activities of simpler carboxylic acids not only involved mixtures of the latter but possibly erroneous structural identification. Our X-ray structure analyses have shown that the geometric structures reported as estrogenically very active may well have been misidentified. Based on the recent report of the anti-breast tumor activity of 2-methoxyestradiol, we have completed the synthesis of the corresponding 2-methoxybisdehydrodoisynolic acid, which we hope will exhibit anti-cancer activity in males. We have patented our results illustrating the utility of doisynolic-acid-type compounds as weight- and appetite suppressing and control agents. Very recently we received a patent covering the use of (+)-Z-BDDA in therapy for prostate cancer and benign prostatic hyperplasia (BPH) with little feminizing effect. Two "stories" of the interdisciplinary medicinal research being carried out in the Meyers Institute appeared recently: "Inner Workings: Tackling Cancer at the Molecular Level," by Marilyn Davis, in Perspectives列.Research and Creative Activities, Southern Illinois University Carbondale, Spring, 2004, pages 18-21; and "Stalking a Killer," by Gregg Scott, in Southern Alumni, SIUAlumni Association, Vol. 66, September 2004, pages 16-18. More recently, our lab studies provided strong evidence that neurological recovery from traumatic brain injury is facilitated by (了)-Z-BDDA.

(2) Synthesis, reaction mechanisms and stereochemistry of rotationally and sterically restricted compounds: e.g. 9-substituted fluorenes. NMR has been useful in identifying the ap and sp rotamers of a large variety of these structures in solution, and X-ray diffraction has unequivocally characterized them in their crystalline state. Initial studies of the interconversion of ap and sp rotamers as a function of solution pH as well as a function of H-bonding with H-donor solvents have already suggested a new area of non-electronic switches.Studies of selective receptor affinities of ap vs. sp rotamers may open new areas for biological activity investigations and therapeutic applications.

(3) Syntheses and mechanisms involving single-electron-transfer (SET) reactions of anions with perhaloalkanes: We have found that the initial halogenation rates are dependent on the rate of anion formation (substrate acidity) and rate of electron transfer from the formed anion. Investigations of new photoinitiated syntheses of ketones via free-radical reactions of alkynes with CBrCl₃, both having originated in these laboratories, are being continued.

(4) X-ray crystallographic studies: We shall continue to determine the precise structures of our synthesized molecules by X-ray crystal diffraction. Our studies have shown the rotational disorder of selective crystalline compounds containing 2-halo-2-propyl groups, which we have tentatively associated with an intramolecular phenomenon. In other X-ray studies we have determined that the failure of crystalline alcohols to melt and recrystallize on cooling is related to their H-bonded molecular packing, and not necessarily their molecular decomposition as often suggested.

Recent Publications et al. illustrating the Institute柳s interdisciplinary research

Abstracts of Publications

Xie, S.,Meyers, C.Y., Robinson, P.D. N,N'-Dicyclohexyl-N-[1(R,S),2(R,S),6(S,R)-2,6-dimethyl-4-(4-methoxyphenyl-3-cyclohexene-1-carbonyl]urea. An unusual crystalline enantiomeric pairing. Acta Crystallogr. 2004, E60,1361-63.

The synthesis of 1(S,R),2(S,R),5(R,S),6(R,S)-2,6-dimethyl-4-(4-methoxyphenyl)-5-ethyl-3-cyclohexenecarboxylic acid was accompanied by the formation of a byproduct shown to differ only by the absence of the 5-ethyl group. That mixture was subjected to an enantiomer resolution process utilizing (-)-menthol and dicyclohexylcarbodiimide (DCC), and the expected diasteriomers of both compounds were formed along with their anhydrides and an unexpected, but related, compound in both cases. The unexpected compound formed from the substrate lacking the 5-ethyl group was unequivocally identified by X-ray analysis as the title compound, C₂₉H₄₂N₂O₃ (I), a result that, together with the NMR spectra, similarly identified the corresponding product from the compound possessing the 5-ethyl substituent. The X-ray structure indicated that in crystalline racemic (I) the two enantiomers were superimposed, one enantiomer differing from the other only in the position of the double bond, a rare phenomenon, associated with the unusual stereochemistry of (I).

Sandrock, P. B., Meyers, C. Y.,Rath, N. P.and Robinson, P. D. Isopropyl 2,4,6-triisopropylphenyl Sulfone. An Aryl Sulfone with Unusual Atom D [PR1] DDeviations from its Phenyl Least-squares Plane. Acta Crystallogr. 2004, E60, o544-546.

Isopropyl 2,4,6-triisopropylphenyl sulfone, C₁₈H₃₀OS (I), was synthesized for the first time. In spite of the bulky isopropyl substituents on both ortho positions, crystalline (I) did not exhibit rotational disorder of the isopropyl group bonded to the sulfonyl. In contrast, the corresponding bromo- and chloroisopropyl groups of crystalline aryl sulfones possessing much smaller di-ortho-methyl substituents displayed striking rotational disorder. While the aryl rings of the latter compounds are essentially planar, considerable atom deviation from the phenyl least-squares plane of (I) was observed. None of the intra- or intermolecular distances between the methyl carbon atoms of the sulfonyl- isopropyl group and those of the two ortho-isopropyl groups of (I) are shorter than the sum of their van der Waals radii, making it unlikely that they would interfere with the rotation of the a-isopropyl group prior to crystallization.

Hou, Y. and Meyers, C. Y., Stereochemistry of Reactions Involving Rotationally Restricted, Sterically Hindered, Cations, Radicals and Anions. 9-Fluorenyl Systems. J. Org. Chem. 2004, 69, 1186-1195.

A study of the stereochemical pathways of reactions involving rotationally restricted, sterically hindered cations, radicals and anions has been undertaken utilizing chiral 9-(o-tert-butylphenyl)fluorenes. Previous reports of studies using these or related achiral compounds contained erroneous or equivocal conclusions. This study shows that (+)-sp-9-(o-tert-butylphenyl)-9-methoxy-2-methylfluorene, treated with Tf₂O-CHCl₃to form 100% of the 9-cation, then with NaOMe-MeOH, provided 29% of re-formed substrate (configurational retention) and 71% of the (-)-sp enantiomer (inversion). The same substrate treated with HI-CHCl₃ was converted into the 9-radical which was rapidly reduced, affording 100% isolation of (-)-sp-9-(o-tert-butylphenyl)-2-methylfluorene (inversion). Treatment of the latter with n-BuLi-THF provided the 9-anion which, on acidification, yielded 100% of the enantiomeric (+)-sp-9-(o-tert-butylphenyl)-2-methylfluorene (inversion). The substrates in these reactions were the thermodynamically favpred sp rotamers. Inversion directly produced the higher-energy non-enantiomeric ap rotamers, which rapidly rotated into the sp products, that were enantiomeric with the substrates. These results are explained by the rotational restriction and partial steric hindrance by the tert-butyl group to the original face of the sp³ antiaromatic 9-cation (4n p electrons), and the rotational restriction and extensive blockage to the original face of the sp² nonaromatic 9-radical (4n +1 p electrons) and aromatic (4n + 2 p electrons) 9-anion. The barrier to rotation in some of the ortho-substituted 9-arylfluorenes is great enough to allow their sp and ap rotamers to be detected coexisting in solution, although their crystals were composed exclusively of one. Rotational restriction and steric hindrance at the 9-position have a large influence on the pK_a values of these fluorenes and can offset the classic electronic effects of the substituents.

Meyers, C. Y.; Robinson, P. D.; McLean, A.W, sp-9-(o-Methylphenyl)fluorene, Acta Crystallogr. 2004, C60, o156-157.

While the barriers of rotation of the sp and ap rotamers of 9-(o-methylphenyl)fluorene, C₂₀H₁₆, are sufficiently similar to permit them to equilibrate, both being observed (NMR) in solution, crystallization provides the sp rotamer (I) exclusively. Although in the sp conformation the intramolecular distance between adjacent C atoms of phenyl and fluorene rings is very small, in the ap conformation the distance between the adjacent o-CH₃ group on the phenyl ring and C atom on the fluorene ring would be much closer, based on that exhibited in the crystalline ap progenitor, 9-(o-methylphenyl)-9-fluorenol. The angle between the fluorene and 9-aryl planes of (I) is 75.82 (10)翄.

McLean, A. W., Meyers, C. Y., and Robinson, P. D., 9-(p-Methylphenyl)fluorene, Acta Crystallog. 2004,E60, o75-76.

9-(para-Methylphenyl)fluorene, C₂₀H₁₆,(II), displays no unusual characteristics. The aryl and fluorenyl rings are midway between exhibiting perpendicularity and coplanarity. Neither intermolecular hydrogen bonding nor strong aryl-H^列 [PR2] p(arene) interaction is exhibited, which conforms with the rapid recrystalization of the melted crystals on cooling.

Robinson, P.D., McLean, A.W., Meyers, C.Y. 9-(p-Methylphenyl)-9-fluorenol, Acta Crystallogr. 2003, E59, o1915-1917.

The title compound, C₂₀H₁₆O, exhibits two nearly identical conformtions in its asymmetric unit, joined via OH^列O-H as well as O-H^列p (fluorene) intermolecular H-bonds. The 9-aryl and fluorene rings of both structures are substantially away from perpendicularity. Although the crystals melt sharply without molecular decomposition, the melt fails to recrystallize when cooled even after a long period. Similar phenomena are observed with other crystalline 9-alkylphenyl-9-fluorenols that exhibit intermolecular p (arene) interactions.

Meyers, C. Y., Robinson, P. D. and McLean, A.W., ap-9-(o-Methylphenyl)-9-fluorenol, a Structure exhibiting several Aryl-H^列p(arene) intermolecular Interactions.Acta Crystalogr. 2003, C59, o712-714.

The title compound, C₂₀H₁₆O, (I), which crystallized exclusively as its ap rotamer, exhibits several intermolecular aryl-H^列p(arene) interactions, resulting in planar molecular arrays in which each molecule interacts with six adjacent molecules. Surprisingly, there were no O-H^列O-H or O-H^列p(arene) interactions within hydrogen-bonding distances. Crystalline (I) melted sharply without molecular decomposition (NMR), but the cooled melt recrystallized only after several hours.

McLean, A. W., Meyers, C. Y. and Robinson, P. D. sp-9-(meta-Methylphenyl)-9-fluorenol, 2003, Acta Crystallogr E59, o1228-1230.

The title compound. C₂₀H₁₆O (I), whose 9-aryl group is freely rotating in solution, crystallized exclusively as its sp rotamer, which exhibited intermolecular H-bonding involving O-H^列p(fluorene) but not involving O-H^列OH. The molecules pack as dimers incorporating two O-H^列p(fluorene) hydrogen bonds. Although (I) melted sharply without decomposition, its melt failed to recrystallize on cooling.

Robinson, P. D., McLean, A. W. and Meyers, C. Y. ap- 9-(meta-tert-Butylphenyl)fluorene, Acta Crystallogr. 2003, C59, o539-540.

The title compound, C₂₃H₂₂ (I), crystallizes in its ap conformation and its melt readily recrystallizes on cooling, in contrast to its corresponding 9-fluorenol (II), which is sp and melts undecomposed but fails to recrystallize over a long period. Both of these differences are here ascribed to the intermolecular H-bonding in (II) which is absent in (I), leading to distinctly different molecular packing in the two compounds.

Meyers, C. Y., McLean, A. W., Robinson, P. D. 9-(meta-tert-Butylphenyl)-9-fluorenol, Acta Crystallogr. 2003, E59, o978-980.

The title compound, C₂₃H₂₂O, is composed of molecules bonded into linear one-dimensional chains through O-H^列p(fluorene) hydrogen bonds, each molecule being both H-donor and -acceptor. No O-H^列O-H hydrogen bonding was exhibited, despite the close donor-O列acceptor-O distance [2.849 (3) Å]. The melted crystals failed to recrystallize on cooling, although solution NMR showed that no decomposition had occurred during the melting.

McLean, A. W., Meyers, C. Y., Robinson, P. D. 9-(para-tert-Butylphenyl)-9-fluorenol, Acta Crystallog. 2003, E59, o891- o893.

The title compound, C₂₃H₂₂O, [PR3] is composed of two slightly different molecular conformations [PR4] within its asymmetric unit,one conformation hydrogen bonded to the other via their OH groups. The two molecular conformers are reproduced by an inversion center and hydrogen bonded through an O-H^...p (fluorene) bond, thus producing groups of four hydrogen-bonded molecules. The cooled melted crystals failed to recrystallize, but solution NMR showed that no chemical decomposition had occurred during the melting.

Ganguly, A., Meyers, C. Y., Robinson, P. D. 2-Acetylphenylboronic Acid Monohydrate. Acta Crystallog. 2003, E59, o-759-o761,

The title compound,C₈H₉BO₃^.H₂O_, displays extensive intermolecular H-bonding of molecules of 2-acetylphenylboronic acid with each other and with molecules of water, producing infinite, 2-dimensional molecular layers. There is no intramolecular H-bonding between the ortho C=O and (HO)₂B substituents.

Xie, S., Yuqing Hou, Y.,Meyers, C. Y. and Robinson, P. D. Lactone precursors of prostate therapy agents. I. (了)-anti-7-Ethyl-1-(4-methoxyphenyl)-5,5,syn-8-trimethyl-2-oxabicyclo[2.2.2]octan-3-one, a bicyclic d_lactone. Acta Crystal- ;log. 2003, E59, o-403-405.

The titled bicyclic d-lactone (I) (C₁₉H₂₆O₃) was formed in the reaction of (了)-cis-2,6,6-trimethyl-trans-3-ethyl-4- oxocyclohexane- carboxylic acid with p-methoxyphenylmagnesium bromide, following acidification. Kinetically favored lactone (I) was formed rapidly but reversibly, allowing the thermodynamically favored g-lactone to be formed and isolated after a longer treatment with acid. The expected corresponding carboxylic acids were not isolable under these conditions. In lactone (I), basically composed of an aromatic ring

appended to a [2.2.2] bicyclic system, the O-C(O)-C group is asymmetric, its O-C=O angle being 119.46(19)˚and its O=C-C angle being 127.82(19)˚.

Xie, S., Yuqing Hou, Y.,Meyers, C. Y. and Robinson, P. D. Lactone precursors of prostate therapy agents. II. (了)-5-Ethyl-endo-4-(4-methoxyphenyl)-2,2,anti-8-trimethyl-6-oxabicyclo[3.2.1]octan-7-one, a bicyclic g-lactone Acta Crystallog. 2003, E59, o-406-407.

The titled bicyclic g-lactone (II) (C₁₉H₂₆O₃), the thermodynamically favored lactone, was formed in the reaction of (了)-cis-2,6,6-trimethyl-trans-3-ethyl-4-oxocyclohexanecarboxylic acid with p-methoxyphenylmagnesium bromide, following prolonged treatment under acidic conditions. The kinetically favored isomeric (了)-d-lactone (I) was described in the previous report. In lactone (II), basically composed of an aromatic ring appended to a [3.2.1] bicyclic system, the O-C(O)-C group is asymmetric, its O-C=O angle being 120.80(15)˚ and its O=C-C angle being 130.46(16)˚.

Meyers, C. Y.,Chan-Yu-King, R., Hua, D. H., Kolb, V. M., Matthews, W. S., Parady, T. E., Horii, T., Sandrock, P. B.,Hou, Y. and Xie, S. Unexpected Differences in the a-Halogenation and Related Reactivity of Sulfones with Perhaloalkanes in KOH-t-BuOH. J. Org. Chem. (2003), 68, 500珻511.

Most alkyl phenyl sulfones are readily a-chlorinated with CCl₄ and a-brominated with CBrCl₃in KOH-t-BuOH via radical-anion radical pair (RARP) reactions. While isopropyl mesityl sulfone (4) is easily a-chlorinated with CCl₄, it was completely recovered when treated with the more reactive CBrCl₃. Subsequent investigations showed the latter result to be due to the poor acidity of 4 togther with the rapid depletion of CBrCl₃and KOH by their reaction with each other, and led to a variety of other important results. 4-Hydroxyphenyl isopropyl sulfone (6) is unreactive with either CCl₄ or CBrCl₃ in KOH-t-BuOH, its phenoxide anion strongly reducing the electronegativity of the sulfonyl group, thereby inhibiting a-anion formation. This effect is reversed by the electron-withdrawing influence of two a-phenyls, so that benzhydryl 4-hydroxyphenyl sulfone (8) is readily a-halogenated in KOH-t-BuOH with CCl₄ or CBrCl₃.On further contact with halogenated derivatives of 4-methoxyphenyl benzhydryl sulfone (9) are stable to base, they are decomposed even under mildly acidic conditions into 4-methoxyphenyl 4-methoxyben- zenethiol sulfonate (9c), phenol, and benzophenone. Mono a-halogenation of benzyl phenyl sulfone (10) enhances the rate of the subsequent halogenation, so that a.a-dihalogenation is attained while much substrate is still present and the mono-a-halogenated product is not detected. The ease of reductive debromination of abromo sulfones with Cl₃C^-was correlated with the stability of the formed a-anions, explaining the success with a-bromo- benzylic sulfones but failure with a-bromoalkyl sulfones. In the presence of air and the absence of competing halogenation, formation of the a-anions of alkyl aryl sulfones is quickly accompanied by oxidative cleavage by atmospheric O₂, leading to the formation of arenesulfonyl alcohols, arenesulfonyl halides and haloarenes.

Robinson, P. D., Meyers, C. Y. and Kolb, V. M. Cyclohexyl Phenyl Ketone, Acta Crystallogr. 2002, E58, o-1288-1289.

The C⁼O bond of the title compound (C₁₃H₁₇O) is essentially coplanar with the phenyl ring. The cyclohexyl ring is in the chair conformation and its least-squares plane is at an angle of 55.48 (9)翄 to the phenyl ring. No intermolecular H-bonding is exhibited.

Meyers, C. Y., Roper, W., Klavetter, F., Horii, T., Sandrock, P. B. and Robinson, P. D. 2-Propyl Mesityl Sulfone, Acta Crystallogr. 2002, E58, o-1166-o1168.

2-Propyl mesityl sulfone (I) is entirely devoid of the rotational disorder displayed in the corresponding 2-bromo- and 2-chloro-2-propyl mesityl sulfones. Each molecule hydrogen bonds with four mirror-image molecules, each utiliizing the acidic a-hydrogen atom

of its 2-propyl group and a p-methyl-hydrogen atom as well as its two sulfonyl-oxygen atoms as acceptors. Its molecular packing exhibits continuous chains of intermolecular hydrogen bonds involving both sulfonyl oxygen atoms, with the acidic 2-propyl hydrogen atom and a p-methyl-hydrogen atom, respectively.

Kolb, V. M., Donahue, M. G. Putnam, E. A., Meyers, C. Y. and Robinson, P. D. Cyclopropyl m-Nitrophenyl Ketone, Acta Crystallogr. 2002, E58, o1161-1163.

The title compound exhibits coplanarity of the phenyl plane with the C⁼O bond and O-N-O plane. Through the oxygen atoms of the carbonyl and nitro groups and the hydrogen atoms of the phenyl rings, a network of intermolecular hydrogen bonds involves each molecule with four other molecules. The result is a structure composed of discrete, two-dimensional, H-bonded molecular layers.

Meyers, C. Y., Hou, Y., Winters, T. A., Banz, W. J. and Adler, S. Activities of a Non-classical Estrogen, Z-Bis-dehydrodoisynolic Acid, with ERa and ERb. J. Steroid Biochem. Mol. Biol. 2002, 82, 33-44.

(了)-Z-bisdehydrodoisynolic acid [(了)-Z-BDDA] is highly estrogenic in vivo, yet binds to estrogen receptor (ER) poorly. This paradox has raised the possibility of alternative ERs and/or molecular mechanisms. To address the possibility of high activities of Z-BDDA with ERb, we determined the activities of (+)- and (-)-Z-BDDA, in cell culture and in vitro, comparing ERb to ERa. Transfectional analysis in Hela cells showed (-)-Z-BDDA is an agonist for gene activation with both ERa (EC₅₀@ 0.3 nM) and ERb (EC₅₀ @ 5 nM), while little to no activity was observed with (+)-Z-BDDA. Similarly, in gene repression assays, (-)-Z-BDDA was active (EC₅₀ @ 0.2 nM), but again minimal activity was exhibited by (+)-Z-BDDA. Binding to ERa and ERb in vitro used both competition and a direct binding assay. For ERa, the relative affinity of (-)-Z-BDDA was approximately 0.06 by competition and 0.017 by direct binding vs E2, while (+)-Z-BDDA also demonstrated binding, but with relative affinities of only 0.0008 by competition and 0.003 by the direct assay. For ERb, the affinity of (-)-Z-BDDA was approximately 0.07 by competition and 0.015 by the direct assay relative to E2, while (+)-Z-BDDA had lower affinity, approximately 0.002 that of E2 by both assays. The paradox of potent in vivo activity but lower activity in receptor binding and in culture reporter gene assays, previously seen with ERa is now also associated with ERb. The failure of ERb to explain the activity-binding paradox indicates the need for additional in vivo metabolic and pharmacokinetic studies and continued consideration of alternative mechanisms.

Chan-Yu-King, R., Anil, J., Meyers, C. Y. and Robinson, P. D. Dichloromethyl Phenyl Sulfone Acta Crystallogr, 2002. E58, 592-595.

The unequivocal structure of dichloromethyl phenyl sulfone (I) (C₇H₆Cl₂O₂S) via X-ray analysis is reported for the first time. Prepared from the reaction of sodium benzenesulfinate with chloroform in KOH, (I) exhibited a sharp melting point, 331.5-332 K. Several different melting points have been reported. We find that (I) crystallizes as two chemically identical molecules in the aymmetric unit, but with a number of small geometric variations between the two molecules. Intermolecular Cl₂CH^...O^_S(O)^_Ph hydrogen bonding between molecules produced infinite molecular chains, which may induce the small geometric differences exhibited in the two molecules of (I).

Xie, S., Hou, Y., Meyers, C. Y. and Robinson, P.D. Cis-2-methyl-trans-3-ethyl-6,6-dimethyl-4-ketocyclohexane- carboxylic Acid. An Intermediate in the Synthesis of a Highly Potent Estrogen. Acta Crystallogr.2002, C58, o159-161.

The title compound (IV), whose ethyl ester is an intermediate in the synthesis of a compound reported to be highly estrogenic, was prepared. After the initial steps reported for the synthesis of this ester intermediate were followed, it was converted into its crystalline acid (IV) for X-ray analysis which indicated that the crystal selected contained a single enantiomer. However, the presence of racemic acid IV in solution was verified; thus the crystal is more likely an inversion twin. X-ray analysis showed that anti-hydrogenation of the double bond had occurred in the synthesis, making the orientation of the carboxyl group cis to the 2-methyl group and trans to the 3-ethyl group. NMR showed that the stereochemistry of IV and its ester precursor was identical. While the stereochemistry of this ester was not noted in the earlier report, it pointed out that the estrogenic product derived from it possessed the opposite carboxyl-2-methyl orientation, i.e. trans, although no X-ray analysis was performed. In light of these results and the importance of correlating biological activity with compound structure, the unequivocal characterization of the highly estrogenic compound is warranted.

Wilson, T., March, H., Banz, W. J., Hou, Y., Adler, S., Meyers, C. Y., Winters, T.A. and Maher, M. A. Antioxidant Effects of Phyto- and Synthetic Estrogens on Cupric Ion-Induced Oxidation of Human Low Density Lipoproteins In Vitro. Life Sciences, 2002, 70, 2287-2298.

Oxidation of low density lipoproteins (LDL) stimulates atherosclerotic plaque formation. Estrogenic compounds (ELC) from food and other natural products, and synthetic estrogenic compounds (SECs) products may prevent heart disease by preventing LDL oxidation In the present study, we tested the antioxidant capacities of two phyto estrogens, daidzein (DAI) and genistein (GEN), and four SEC's, (+)- and (-)-Z-bisdehydrodoisynolic acid (ZBDDA), and (+)- and (-)-hydroxy-allenolic acid (HAA), on isolated human LDL subjected to oxidation by cupric sulfate. The effects of these estrogenic compounds on the kinetics of conjugated diene formation in LDL undergoing oxidation were evaluated by using a lag-time assay with continuous monitoring of absorbance at 234 nm. Lagtime data revealed that (+)-HAA, (-)-HAA, (+)-ZBDDA, and (-)-ZBDDA had similarly stronger antioxidant activities than either GEN or DAI. We also found that (+)-HAA, (-)-HAA, (+)-ZBDDA, and (-)-ZBDDA strongly inhibited the formation of Cu⁺⁺-induced thiobarbi ituric acid reactive substances (TBARS) in LDL, and that GEN and DAI were less effective for inhibiting LDL lipid peroxidation, and electrophorwtic evaluation suggested that, relative to GEN and DAI, the apo-lipoprotein B-100 of LDL was better protected against oxidation by (+)- HAA, (-)-HAA, (+)-ZBDDA, and (-)-ZBDDA. In summary, the four synthetic estrogenic compounds, (+)-HAA, (-)- HAA, (+)-ZBDDA, and (-)-ZBDDA, were more potent antioxidants than the phytoestrogens, DAI and GEN.

Xie ,S.,Hou,, Y.,Meyers, C. Y.,and Robinson, P. D. 2(S),6(R)-Dimethyl-4-(4-methoxyphenyl)-5(R)-ethyl-3-cyclohexene-1(S)-carboxylic acid and its enantiomer - potential therapeutic agents for prostate cancer. Acta Crystallogr. 2002, E58, o1460-o1462.

The synthesis, isolation, and definitive diasteriomeric characterization of the racemic title compound (I) (C₁₈H₂₄O₃) was accomplished. The two enantiomers of I are hydrogen bonded with each other through their respective carboxylic-acid groups, forming an octagonal bridge. A preliminary study indicates that (I) definitely inhibits prostate cancer-cell proliferation

Robinson,P. D., Parady, T. E., Hou, Y. and Meyers, C. Y. 2-Bromo-2-propyl Phenyl Sulfone. Acta Crystallogr. 2001, E57, o584-o586.

Crystalline 2-bromo-2-propyl phenyl sulfone (a-bromoisopropyl phenyl sulfone) C₉H₁₁BrO₂S exhibits no rotational disorder of its a-bromoisopropyl group in contrast to the large disorder of the same group exhibited by crystalline 2-bromo-2-propyl mesityl sulfone.

Meyers, C. Y., Hua, D. H., Hou, Y. and Robinson, P. D. 2-Chloro-2-propyl mesityl sulfone. Acta Crystallogr. 2001, E57, o587- 589.

Crystalline 2-chloro-2-propyl mesityl sulfone (a-chloroisopropyl mesityl sulfone), C₁₂H₁₇ClO₂S, exhibits much less rotational disorder of its a-chloroisopropyl group than that exhibited by the a-bromoisopropyl group in the related crystalline 2-bromo-2-propyl mesityl sulfone

Robinson, P. D., Sandrock, P. B., Xie, Songwenand Meyers, C. Y. 2-Bromo-2-propyl 2-(5-tert-butyl-1,3-xylyl) ketone. Acta Crystallogr. 2001, E57, o555-557.

The 2-bromo-2-propyl (a-bromopropyl) group in crystalline 2-bromo-2-propyl 2-(5-tert-butyl-1,3-xylyl) ketone C₁₆H₂₃BrO, exhibits a surprisingly high degree of rotational disorder, although it is freely rotating in solution.

Chan-Yu-King, R., Hou, Y., Sandrock, P. B., Meyers, C. Y. and Robinson, P. D. 2-Bromo-2-propyl Mesityl Sulfone. Acta Crystallogr. 2001, E57, o449-450.

Crystalline 2-bromo-2-propyl mesityl sulfone (a-bromoisopropyl mesityl sulfone), C₁₂H₁₇BrO₂S, exhibits significant rotational disorder of its a-bromoisopropyl group, although it is freely rotating in solution as demonstrated by NMR.

Robinson, P. D., Lutfi, H. G., Hou, Y. and Meyers, C. Y. 1,1-Di-9-fluorenylethyl Acetate, a Byproduct from the Acetylation of 9-Fluorenyllithium. Acta Crystallogr. 2001, C57, 582-584.

The preparation of sp-9-acetylfluorene from the reaction of 9-fluorenyllithium with acetyl chloride also provided 9-(1-acetoxyethylidene)fluorene ("Diacetylfluorene") and 1,1-di-9-fluorenylethanol (2) as byproducts recently characterized by X-ray analysis. A third byproduct, 1,1-di-9-fluorenylethyl acetate (3), C₃₀H₂₄O₂, has now been unequivocally identified for the first time, and emanates from the acetylation of the oxyanion of (2). In the asymmetric unit, compound (3) exists as two almost identical structures which differ only slightly in conformation. Neither possesses the significant fluorene-ring bowing or the perpendicularity of the two ring planes exhibited by (2). The angle between the least-squares planes of the two fluorene rings of (3) is 58.45 (9) and 60.95 (10)翄, respectively, for the two conformations, and their corresponding bonding parameters also differ slightly in a number of instances.

Meyers, C. Y., Lutfi, H. G., Hou, Y. and Robinson, P. D. 1,1-Di-9-fluorenylethanol, a Byproduct from the Acetylation of 9-Fluorenyllithium. Acta Crystallogr. 2001, C57, 580-581.

Treatment of 9-fluorenyllithium with acetyl chloride produces 9-acetylfluorene (1) and several byproducts. Among them is a com- pound unequivocally identified for the first time as the addition product of (1) with 9-fluorenyllithium,1,1-di-9-fluorenylethanol (2), C₂₈H₂₂O. The two fluorene-ring least-squares planes of (2) are essentially perpendicular [89.90 (9)˚]. A number of intermolecular non-bonding distances are well within or close to the sum of their respective van der Waals radii and may be responsible for the rarely observed large bowing of one of the fluorene rings. This bowing apparently arises from two molecules impinging on the convex face of the bowed ring, augmented by hydrogen bonding between the peripheral 宪 electrons of the concave face and the hydroxyl H atom of another molecule adjacent to that face.

Robinson, P. D., Lutfi, H. G., Hou, Y. and Meyers, C. Y. 9-(1-Acetoxyethylidene)fluorene ("Diacetylfluorene"), a Byproduct from the Acetylation of 9-Fluorenyllithium. Acta Crystallog. 2001, C57, 428-430.

Treatment of 9-fluorenyllithium with acetyl chloride produces 9-acetylfluorene (1) and several byproducts, among which is "diacetylfluorene," now characterized definitively as 9-(1-acetoxyethylidene)fluorene (2), C₁₇H₁₄O₂, derived from acetylation of initially formed (1). Various parameters disclose substantial structural distortion within (2) emanating from A(1,3) strain associated with the 9-(acetoxyethylidenyl)fluorene system.

Meyers, C. Y., Lutfi, H. G., Varol, P., Hou, Y. and Robinson, P. D. Preparation and Surprising sp Rotameric Structure of 9-Methyl-9-pivaloylfluorene. Acta Crystallogr. 2000, C56, 1468-1470.

Methylation of 9-lithiated ap-9-pivaloylfluorene (1) as well as pivaloylation of 9-lithiated 9-methylfluorene provided rotationally stable sp-9-methyl-9-pivaloylfluorene (3), C₁₉H₂₀O. Fluorene (1) exists exclusively in the ap configuration in solution (NMR) as well as in the crystalline state, reflecting the unfavorable interaction between the tert-butyl and fluorene-ring 宪 electrons in the sp configuration. The existence of (3) exclusively in the sp configu-ration indicates that in this case the interaction between the tert-butyl group and the fluorene-ring 宪 electrons provides relatively more thermodynamic favorability than the steric interaction between the tert-butyl and 9-methyl groups (ap configuration).

Robinson, P. D., Lutfi, H. G., Hou, Y. and Meyers, C. Y. Unexpected Dipivaloylation of 9-lithiated fluorene. Formation of 9-(2柳,2柳-dimethyl-1柳-pivaloxypropylidine)fluorene. Acta Crystallogr. 2000, C56, 1380-1382.

Treatment of 9-lithiated fluorene with pivaloyl chloride provided ap-9-pivaloylfluorene (1), the major product, and a minor product ultimately identified as 9-(2柳,2柳-dimethyl-1柳-pivaloxy-propylidine)fluorene C₂₃H₂₆O₂, (2). The latter was also formed directly, but slowly, from 9-lithiated-(1) treated with pivaloyl chloride. Although (1) exists

exclusively as its less sterically restricted ap rotamer, its sp-2-hybridized anion sterically impedes reaction at the 9-position from either face. While 9-lithiated-(1) is exclusively, but slowly, 9-methylated with methyl iodide, reaction with pivaloyl chloride is also slow but leads only to the O-acylated product, (2). The protons of the tert-butyl-C=C moiety approach a proton on the fluorene ring to well within the sum of their van der Waals radii, resulting in significant molecular compression, strain and distortion. For example, distortion in the moiety C=C(O)(C) is exhibited by enlargement of angle C=C-C to 130.6 (2)˚ at the expense of the corresponding "equivalent" angle C=C-O, which is compressed to 116.46 (19)˚.

Meyers, C. Y., Hou, Y., Robinson, P. D., Adler, S., Banz, W. J. and Winters, T. A. Absolute Structure Determination of the Highly Biologically Active Bisdehydrodoisynolic Acids. J. Pharm. Sci. 2000, 89, 513-518.

In a project designed to relate the unexpected in vivo and in vitro properties exhibited by (+)- and (-)-bisdehydrodoisynolic acid with their absolute stereochemical structure, an X-ray crystal-structure analysis was undertaken of the highly estrogenic, poorly binding (-) enantiomer. ¹H and ¹³C NMR spectra are also reported for the first time. The crystal structure shows the cis juxtaposition of the carboxy and ethyl groups, which are separated by a large torsion angle, and that only the carbon atom holding the carboxyl group is out of the plane in which the remainder of the fused three-ring moiety lies. The crystal structure, which unequivocally characterizes the (-) and, implicitly, the (+) enantiomer, will be useful in continued studies aimed at explaining the selective estrogen receptor modulation (SERM) of these enantiomers which, in some cases, produces significantly different end-organ effects compared to those of estradiol, in both males and females, affording the promise of a variety of therapeutic and pharmacologic applications.

Hou, Y. and Meyers, C. Y. The First One-pot Asymmetric Synthesis of Esters of Highly Biologically Active (+)- and (-)-3-[2-(6-Methoxynaphthyl)]-2,2-dimethylpentanoic Acid (Vallestril®). ARKIVOC (On-Line Journal of Organic Chemistry), 2000, 1, 95-102.

Our recent studies on the biological activity of (+)- and (-)-3-[2-(6-hydroxynaphthyl)]-2,2-dimethylpentanoic acid led to several intriguing discoveries that warrant further investigation. As a result it became advisable to provide a straightforward, efficient asymmetric synthesis of these enantiomeric acids. Thus, for the first time, a one-pot asymmetric synthesis of esters of the two acids was designed and carried out, involving Michael addition followed by methylation. With (-)-menthyl as the chiral auxiliary group, 77% of the desired diastereomeric products was obtained, but without stereoselectivity. When the chiral auxiliary group was (-)-8-phenylmenthyl, the yield, based on consumed starting material, was 77%, with a de value of 26% determined by ¹H NMR. Further work to optimize the reaction conditions to improve the yield and de value is underway.

Meyers, C. Y., Hou, Y., Lutfi, H. G. and Saft, H. L. The First Reported Halogenation of a tert-Butyl Group with HCl or HBr in CHCl₃. Unexpected Differences in the Reactions of HCl, HBr, HI and HF with sp-9-(o-tert-Butylphenyl)-9-fluorenol. J. Org. Chem. 1999, 64, 9444-9449.

The reactions of sp-9-(o-tert-butylphenyl)-9-fluorenol (1) with HCl, HBr, HI, and HF, respectively, were found to follow diverse pathways. Most unexpected is the unprecedented monohalogenation of a tert-butyl group, sp-9-[o-(b-chloro-a,a-dimethylethyl)phenyl]fluorene (2) being formed quantitatively from (1) treated with HCl-CHCl₃, and sp-9-[o-(b-bromo-a,a-dimethylethyl)phenyl]fluorene (3) (>90%) along with a very small amount of sp-9-(o-tert-butylphenyl)fluorene (4) being formed from (1) treated with HBr-CHCl₃. The absolute structure of (2) was ascertained by X-ray crystal analysis. Likewise, the expected 9-chloro- and 9-bromofluorenes from the usual substitution of OH by halogen in reactions of alcohols with SOCl₂ and SOBr₂ were not obtained from treatment of (1) with these reagents; the only products were (2) and (3), respectively. These products are formed by nucleophilic attack of halide ion on a tert-butyl methyl group of the 9-cation (1a) with concerted intramolecular displacement of hydride to 9-C⁺, while (4) results from the slower electron transfer from Br^- to (1a) to form free radical (1b), which captures an H atom from HBr. The high redox potential of I^-and weak HI bond ensures the rapid conversions (1a) 哩 (1b) 哩 (4), making (4) the exclusive product from treatment of (1) with HI-CHCl₃. In contrast to the other halides, fluoride is a poor nucleophile indisplacement reactions and poor electron-transfer agent. Consequently, strongly electrophilic 1a reacts with F^- to provide sp-9-(o-tert-butylphenyl)-9-fluorofluorene (5) as the only product from the reaction of (1) with pyridine^.(HF)_x. Dynamic NMR provided strong evidence that the reaction with HI occurs with inversion, the ap rotamer (4a) of 9-(o-tert-butylphenyl)fluorene being formed initially, followed by rotation to the isolated sp rotamer, (4). The largely planar configuration of C-9 of the unsymmetrically hindered cation intermediate (1a), responsible for this inversion and the related inversions, was supported by NMR.

Hou, Y. and Meyers, C. Y., The Surprising Formation of Structurally Distorted ap-9-(o-tert-Butylphenyl)-9-methylthiofluorene and its Facile Homolysis into sp-9-(o-tert-Butylphenyl)-3-methylthio fluorene and sp-9-(o-tert-Butylphenyl)fluorene. Can. J. Chem. 1999, 77, 960-966 (invited paper).

The continued study of rotationally restricted 9-(o-tert-butylphenyl)fluorenes has provided surprising results. Treatment of sp-9-(o-tert-butylphenyl)-9-fluorenol (1) with ethanol or methanol under acidic conditions affords sp-9-(o-tert-butylphenyl)-9-ethoxyfluorene (2b) and sp-9-(o-tert-butylphenyl)-9-methoxyfluorene (3b), respectively,

but similar treatment with methanethiol converts (1) into the rotamerically opposite ap-9-(o-tert-butylphenyl)-9-methylthiofluorene (4a). While all three products reflect reaction with inversion at C-9, (2b) and (3b) reflect subse- quent rotation, which is not the case with (4a). X-ray diffraction shows (4a) to be highly distorted and strained, but apparently favored thermodynamically over its sp rotamer. Homolysis of (4a) is observed at room temperature, and at elevated temperatures accounts for the formation of sp-9-(o-tert-butylphenyl)fluorene (6b) and sp-9-(o-tert-butylphenyl)-3-methylthiofluorene (7c) as major products. X-ray diffraction shows (6b) and (7c) to be virtually devoid of distortion. Methylation of (6b) via its anion also proceeds with inversion without rotation to form ap-9-(o-tert-butylphenyl)-9-methylfluorene (4c). Dynamic NMR unexpecedly showed that in these ap configurations 9-CH₃ (of 4c) has a greater bulk effect than 9-CH₃S (of 4a) in forcing the o-tert-butyl group into the fluorene plane.

Banz, W. J., Winters, T. A., Hou, Y., Adler, S. and Meyers, C. Y. Comparative Effects of the Selective Estrogen Recep- tor Modulators (-)-, (+)- and (^了)-Z-Bisdehydrodoisynolic Acids on Metabolic and Reproductive Parameters in Male and Female Rats. Hormone and Metabolic Research, 1998, 30, 730-736.

Doisynolic acids are non-steroidal estrogenic compounds originally obtained from alkali fusion of estrone or equilenin. Z-bisdehydrodoisynolic acids (Z-BDDA) exhibit a low binding affinity accompanied by a dispropor- tionately high biologic activity. Two experiments were designed to investigate the chronic effects of (+)-, (-)- and (^了)-Z-BDDA and 17b-estradiol (E2) in male and female rats. The (+)-, (-)- and (了) forms Z-BDDA were prepared and administered, for four to six weeks, to male and female rats and changes in body weight, food intake, metabolic parameters, and reproductive parameters were investigated. Results from both experiments demonstrate that in male and female rats, (+)- and (^了)-Z-BDDA had similar estrogenic effects on reproductive organ weight. Surprisingly, (-)-Z-BDDA did not induce the increase in uterine weight observed with (+)- and (^了)-Z-BDDA and E2, hence, demon- strating selective estrogen receptor modulation (SERM). Beneficial metabolic effects, although compound- and gender-specific, included a significant weight repression, reduction in cholesterol, reduction in blood glucose, and positive alterations in body fat distribution. Future research defining the optimal dosages of (-)-Z-BDDA that will maximize beneficial effects and minimize undesirable effects on reproductive tissues will lead to more efficacious treatment options for endocrine-responsive conditions in males and females.

Recent Presentations at Professional Meetings

(Authors, presentation title, professional meeting, where, and when presented)

Stuart R Adler, William J Banz. Neil F. Shay,⁴ Jennifer Ross-Viola, Todd A Winters,Yuqing Hou,and Cal Y Meyers. Phytoestrogens and a Non-steroidal Selective Estrogen Receptor Modulator are also Ligands for PPAR-g ENDO 2005, The Endocrine Society's 87th Annual Meeting, in San Diego, CA, June 4-7, 2005.

W,J,.Banz, S. Adler, N.F. Shay, J. Ross-Viola., T.A. Winters, Y. Hou, C.Y. Meyers. Phytoestrogens and a Non-steroidal Selective Estrogen Modulator Are Also Ligands for PPAR-g. Annual (FASEB) Experimental Biology Meeting, San Diego, CA, Apr. 2005.

R.W. Clough,S. Adler, L. Neese, W.J. Banz, A.A. Modglin, C.Y. Meyers, Y. Hou, D.C. Smith. Neurological Recovery from Traumatic Brain Injury is Facilitated by (了)-Z-Bisdehydrodoisynolic Acid [(了)-Z-BDDA], a Non-Steroidal Carboxylic Acid with Estrogenic Activity. Am. Assoc. of Anatomists, "Experimental Biology 2005" meeting, San Diego, CA, Apr. 2005.

Xie, Songwen; Hou, Yuqing.; and Meyers, Cal Y. Synthesis, Diastereomer Identification and Enantiomer Resolution of Non-steroidal Estrogenic Carboxylic Acids for in-depth Structure-Physiology Correlation Study. Am. Chem. Soc. Natl. Meeting, San Diego, CA, Mar. 2005, ORGN 799.

Meyers, Cal Y., Sandrock, Paul B., McLean, Aaron, Robinson, Paul. D. Some Unusual Characteristics of Crystalline Organic Compounds Uncovered by X-Ray Studies, e.g., Rotational Disorder and H-Bonding vs.帘mp (dec.)帘. 34^th Midwest Regional ACS Meeting, Manhattan, KS, Oct. 20-22, 2004. Paper No. 167, Abstracts pages 190-191.

McLean, Aaron W.; Meyers, Cal Y.; Hou, Yuqing; Robinson, Paul D. When are experimentally determined pKa values not real pKa values? 34^th Midwest Regional ACS Meeting, Manhattan, KS, Oct. 20-22, 2004. Paper No 117, Abstracts pages 157-158.

Hou, Yuqing; An Enantiospecific Synthesis of (+)-Z-Bisdehydrodoisynolic Acid. 34^th Midwest Regional ACS Meeting, Manhattan, KS, Oct 20-22, 2004. Paper No 168, Abstracts page 191.

Xie, Songwen; Meyers, Cal Y.; Robinson, Paul D. Unusual enantiomers that differ only in the position of their double bond, and whose crystalline forms appear to be superimposed onto each other. 34^th Midwest Regional ACS Meeting, Manhattan, KS, Oct 20-22, 2004. Paper No 116, Abstracts pages 156-157.

Xie, Songwen*; Hou, Yuqing; Meyers, Cal Y.; Robinson, Paul D. Using X-ray crystallography to study the absolute structures of biologically active organic molecules. Abstracts of Papers, 15^th Midwest Organic Solid-State Chemistry Symposium (MOSSCS XV), Carbondale, IL, June 4-6, 2004,

McLean, Aaron W.; Meyers, Cal Y., Robinson, Paul D. Effect of Hydrogen Bonding in the Crystallization of Several 9-(Alkylphenyl)-9-fluorenols and 珻fluorenes. Abstracts of Papers, 15^th Midwest Organic Solid-State Chemistry Symposium (MOSSCS XV), Carbondale, IL, June 4-6, 2004.

Xie, S., Murphy, L. L.,.Henry, N., Hou, Y., and Meyers, C. Y. Synthesis and Resolution of Small Estrogenic Carboxylic Acids and Lactones for PC-3 and MCF-7 Cell-line Studies.. Am. Chem. Soc. National Meeting, Anaheim, CA, March, 2004, MEDI. Abstract No. 238

Winters, T. A., Davis, J., Higginbotham, A., Hou, Y., Adler, S., Henry, N., Peterson, R., Meyers, C. Y.and Banz, W. J. (+)-Z-Bisdehydrodoisynolic Acids Ameliorates Metabolic Syndrome Risk Factors in Female Zucker Diabetic Fatty (ZDF) Rats. Experimental Biology Meetings, April, 2004.

Henry, N.R., Boudreaux, J., Adler, S., Banz, W.J. Hou, Y., Meyers, C. Y., Murdach, D. and Winters, T. A.. Effects of (+)-Z-Bisdehydrodoisynolic acid on PC-3 Human Prostate Carcinoma Cells. 36th Annual Meeting of the Society for the Study of Reproduction, Cincinnati, OH, July 19-22, 2003.

Henry, N.R., Y. Hou, C.Y. Meyers, D. Murdach, and T.A. Winters. 2003. Effects of (+)-z-bisdehydrodoisynolic acid on the proliferation of PC-3 human prostate carcinoma cells. Proceedings of the 9th Annual Southern Illinois University Molecular and Cellular Biology Symposium, Pere Marquette Lodge, Grafton, IL, Mar. 28, 2003 Oral Presentation Abstract, p. 10.

Meyers, C. Y. and Hou, Y. Unequivocal Determination of the Stereochemistry of Reactions involving Sterically hin- dered Rotationally Restricted 9-Fluorenyl Anions, Radicals and Cations. Am. Chem. Soc. National Meeting, New Orleans, March 2003, ORGN 655.

Xie, S., Hou, Y., Meyers, C. Y. and Robinson, P. D. Synthesis of Small Estrogenic Carboxylic Acids for a Study of their in vivo and in vitro Activities. Am. Chem. Soc. National Meeting, New Orleans, March 2003, ORGN 633.

Hou, Y., McCain, M. and Meyers, C. Y . Synthesis of Racemic 3-[3-(1,7-Dihydroxynaphthyl)]-2,2-dimethylpentanoic Acid, a Bacterial Metabolite of Hydroxy-Vallestril.™ Am. Chem. Soc. National Meeting, New Orleans, March 2003. ORGN 635.

Miller, K.J., S.A. Ellis, M.J. Roeder, Y. Hou, S. Adler, C.Y. Meyers,, W.J.Banz, T.A. Winters. Effects of Bisdehydrdro- doisynolic Acids on Rat Uterine Connective Tissue and Smooth Muscle Composition using a Novel Approach. Proceedings of the 8th Annual Southern Illinois University Molecular and Cellular Biology Symposium, Pere Marquette Lodge, Grafton, IL, Mar. 2, 2002 Poster Abstract. Also presented by Kim Miller for the Proceedings of the 1st Annual SAACS Undergraduate Poster Show, Southern Illinois University, Carbondale, IL, Apr. 20, 2002 (awarded 2^nd place in competition).

Henry, N. R., C. Y. Meyers, Y .Hou, S. Adler, M. J. Roeder, K .J. Miller, D.Murdoch, M. S. Bonkowski, and T. A. Winters. 2002. (+)-Z-Bisdehydrodoisynolic Acid: Paradoxical Effects in the Male Rat Reproductive System. Proceedings of the 8th Annual Southern Illinois University Molecular and Cellular Biology Symposium, Pere Marquette Lodge, Grafton, IL, Mar. 2, 2002 Poster Abstract.

Meyers, C. Y.,* Parady, T. E., Chan-Yu-King, R., Sandrock, P. B., Xie, S., Hou, Y., Hua, D. H. and Robinson, P. D. The Enigma of Rotational Disorder in 2-Halo-2-propyl (haloisopropyl) Groups in their Crystalline Compounds. American Chemical Society National Meeting, Chicago, Aug. 26-30, 2001, Paper No. 441.

Hou, Y.,* Xie, S., Sandrock, P. B. and Meyers, C. Y. Unexpected Reduction of the Carbonyl Group of Aromatic Ketones and Aldehydes by Vinyl Grignard Reagents. American Chemical Society National Meeting, Chicago, Aug. 26-30, 2001, Paper No. 447.

S. Adler, M. J. Roeder, K .J. Miller, D. Murdoch, M. S. Bonkowski, and T. A. Winters. (+)-Z-Bisdehydrodoisynolic Acid: Paradoxical Effects in the Male Rat Reproductive System. Proceedings of the 8th Annual Southern Illinois University Molecular and Cellular Biology Symposium, Pere Marquette Lodge, Grafton, IL,

Henry, N., Hou, Y., Roeder, M.J., Winters, T.A., Banz, W. J., Feldmeier, J., Patton, J., Adler, S., and Meyers, C.Y., Effects of (+)-Z-Bisdehydrodoisynolic Acid on the Rat Prostate. 34th Annual Meeting, Society for the Study of Reproduction, Ottawa, Ont., Canada, July 28- Aug. 1, 2001.

Ellis, S. A.,* Perseli, D., Roeder, M. J., Hou, Y., Adler, S., Meyers, C. Y., Banz, W. J. and Winters, T. A. Effects of Bisdehydrodoisynolic Acids on the Reproductive Histology of Female Rats, 7th Annual Southern Illinois University Molecular and Cellular Biology Symposium, Pere Marquette Lodge, Grafton, IL, Feb. 16, 2001 and 34th Annual Meeting, Society for the Study of Reproduction, Ottawa, Ont., Canada, July 28-Aug. 1, 2001.

Sandrock, P., Meyers, C. Y., Hou, Y., Robinson, P. D. and Hua, H. Reactions of Aryl Acetylenes with CBrCl₃ under UV Irradiation. Am. Chem. Soc. Midwest Regional Meeting, St. Louis, Oct. 25, 26, 2000. Abstract 133.

Hou, Y. and Meyers, C. Y. Preparation and 1H NMR Study of 9-Methoxy-9-pivaloylfluorene Rotamers. Am. Chem. Soc. Midwest Regional Meeting, St. Louis, Oct. 25, 26, 2000. Abstract 134.

Winters, T., Banz, W., Cameron J., McDearmon, M., Debeljuk, L., Huggenvik, J., Collard, M., Meyers, C., Hou, Y., Adler, S. and Dandliker, W. Differential effects of estrogenic carboxylic acids on the the testis and prostate. Annual (FASEB) Experimental Biology Meeting, San Diego, CA, April 18, 2000. Abstract 469.3. FASEB J. 14(4):A652.

Wilson, T., March, H., Banz, W. J., Hou, Y., Adler, S., Meyers, C.Y., Winters, T.A. and Maher, M.A., Antioxidant effects of phyto- and synthetic estrogens on Cu⁺⁺-induced oxidation of human low density lipoproteins (LDL). Endo- crinology-Reproductive Physiology Annual Symposium University of Wisconsin, Madison, September 4, 1998. Poster Presentation Abstract #25. Also presented at the Experimental Biology 99 Conference, Washington, DC, April 17-21, 1999, Abstract C-150 II 676.13.

Banz, W. J., Winters, T. A., Hou, Y., Adler, S. and Meyers, C. Y., Comparative Effects of the Selective Estrogen Receptor Modulators (-)-, (+)- and (^了)-Z-Bisdehydrodoisynolic Acids on Metabolic and Reproductive Parameters in Male and Female Rats. Endocrinology-Reproductive Physiology Annual Symposium University of Wisconsin, Madison, September 4, 1998. Poster Presentation Abstract #1.

Suttner, A. M., Banz W. J ., Hou, Y.., Meyers, C. Y., Adler, S. and Winters, T. A. The Effects of Z-Bis-dehydrodoisy- nolic Acids on In Situ Apoptosis in Primary Porcine Granulosa Cells. Endocrinology-Reproductive Physiology Annual Symposium University of Wisconsin, Madison, September 4, 1998. Oral Presentation Abstract #8.

Meyers, C. Y., Hou, Y., Sandrock, P., Robinson, P. D., Hua, D. H. and Chan-Yu-King, R., Solved: The Mesityl Isopropyl Sulfone Enigma, Amer. Chem. Soc. National Meeting, Boston, August 23-28, 1998, Abstract ORGN 637.

Banz, W. J., Winters, T. A., Hou, Y., Meyers, C. Y., Mallon, M. A. and Adler, S. Activities of Non-classical Estrogens: Effects of (-)-, (+)-, and (^了)-Z-Bisdehydrodoisynolic Acids in vitro and on body weight in Male and Female Rats, The Endocrine Society Annual Meeting, June 1998, New Orleans; Abstract P1-552.

Meyers, C. Y. and Adler, S., Estrogenic Activities of Environmental Endocrine Disruptors. The Endocrine Society, 79th Annual Meeting, Minneapolis, June 1997.

Meyers, C. Y., Hou, Y., Lutfi, H. G., Robinson, P. D., Dunn, H. E. and Seyler, J. W. 9-Substituted 9-(o-t-Butylphenyl)- fluorene Rotamers: Reactivity, Dynamic NMR, X-Ray Crystal Structure and Theoretical Studies. American Chemical Society, National Meeting, San Francisco, April 13-17, 1997, Abstracts ORGN 351.

Meyers, C. Y., Hou, Y., Scott, D., Robinson, P. D., Dunn, H. E. and Seyler, J. W. 9-Substituted 9-(o-i-Propylphenyl)- fluorene Rotamers: Reactivity, Dynamic NMR, X-Ray Crystal Structure and Theoretical Studies. American Chemical Society, National Meeting, San Francisco, April 13-17, 1997, Abstracts ORGN 352.

Patents Obtained by Meyers group and collaborators at SIU and generally assigned to SIU initially.

Meyers, C. Y.; Banz, W. J.; Winters, T. A.; Hou, Y.; Adler, S. R. and Dandliker, W. B. Method for Treating or Preventing Prostatic Conditions. Therapeutic Applications of Estrogenic Carboxylic Acids. U.S. Patent 6,608,111, issued August 19, 2003; assigned to Southern Illinois University, The present invention, comprising administering (+)-Z-bisdehydrodoisynolic acid, provides a method for treating, inhibiting or delaying the onset of prostatic conditions including prostatitis, benign prostatic hypertrophy, prostate cancer and other related pathological conditions in patients, and is without accompanying feminizing effects.

Meyers, C. Y. Doisynolic-Acid Type Compounds as Weight and Appetite Suppressing and Control Agents. Filing date July 29, 1993 U.S. Patent 5,420,161, 8 claims, issued, May 30, 1995.

Meyers, C. Y. Doisynolic-Acid Type Compounds as Nontoxic and Noncarcinogenic Antiestrogens,, Antitumor Agents and Hypochlolesterolemic Agents. U.S. Patent Application completed; returned by Patent Lawyer Dec. 10, 1993 to be edited for filing with the U.S. Patent Office.

Meyers, C. Y.; Read, R. B. Process for Cleaning of Coal, Separation of Mineral Matter and Pyrite Therefrom, and Composition Useful in the Process. Attorney file No. 1265; U.S. Patent Application Ser. No. 07/395,014; filed on Aug. 17, 1989; Patent Office allowance of 35 claims, December 13, 1990 (assigned to inventors); issued as U.S. Patent 5,022,983 on June 11, 1991.

Meyers, C. Y.; Chan-Yu-King, R. Process for Preparation of Deuterated Methylene Chloride. Japan, Application, Ser. No. P62-117236, May 15, 1987 (assigned to inventors).

Meyers, C. Y.; Chan-Yu-King, R. Process for Preparation of Deuterated Methylene. Canada, Application Ser. No. 536,874, May 12, 1987; all claims allowed and accepted, July 17, 1990; Canadian Patent 1,283,131 issued April 16, 1991 (assigned to inventors).

Meyers, C. Y.; Chan-Yu-King, R. Process for Preparation of Deuterated Methylene Chloride. European Patent (E.P.O: Italy, France, United Kingdom, West Germany, Switzerland, and Liechtenstein), E.P.O. Patent No. 0 246 805, May 9, 1990 (assigned to inventors).

Meyers, C. Y.; Chan-Yu-King, R. Process for Preparation of Deuterated Methylene. 37 claims. U.S. patent 4,967,021, Oct. 30, 1990 (assigned to inventors).

Meyers, C. Y.; Ho, L. L. Synthesis of a,b-Unsaturated Sulfonic Acid Derivatives. Japanese Patent 973405; Sept. 28, 1979 (assigned to Southern Illinois University Foundation to 1989; assignment transferred to inventors in 1990).

Meyers, C. Y.; Matthews, W. S. Reactions Involving Carbon Tetrahalides and a-Methyl Ketones or Ketones Having a,a'-Hydrogens. U.S. Patent 3,953,494; April 27, 1976 (assigned to Southern Illinois University Foundation); 9 pages.

Meyers, C. Y.; Matthews, W. S.; Malte, A. M. Process for Producing Aryl a-Haloalkyl Sulfones. U.S. Patent 3,949,001; April 6, 1976 (assigned to Southern Illinois University Foundation); 6 pages

Meyers, C. Y.; Malte, A. M. 3-Dihalomethyl-1-Carboxy-1,2,2-rimethylcyclopentane. U.S. Patent 3,896,164; July 22, 1975 (assigned to Southern Illinois University Foundation); 5 pages

Meyers, C. Y.; Ho, L. L.; One-Step Synthesis of Alpha, Beta-Unsaturated Sulfonate Salts by the Reaction of Carbon Tetrahalides with Certain Sulfones. U.S. Patent 3,876,689; April 8, 1975 (assigned to Southern Illinois University Foundation); 11 pages.

Meyers, C. Y.; Matthews, W. S.; Malte, A. M. Reactions Involving Carbon Tetrahalides with Sulfones. U.S. Patent 3,830,862; August 20, 1974 (assigned to Southern Illinois University Foundation); 5 pages.

For more information about the Meyers Institute, graduate, postdoctoral and sabbatical-leave research in the Institute, and applications for carrying out graduate work at SIU in the Institute, please contact us by regular mail or by phone, fax, or e-mail, at the address/numbers provided above. If you have any questions or comments, please feel free to contact institute webmaster:

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