Abstracts of Selected Recent Publications

  1. 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, Ms No. SX 1121, In press.
    Abstract: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)¡, respectively, for the two conformations, and their corresponding bonding parameters also differ slightly in a number of instances.

  2. Meyers, C. Y., Lutfi, H. G., Hou, Yuqing and Robinson, P. D. 1,1-Di-9-fluorenylethanol, a Byproduct from the Acetylation of 9-Fluorenyllithium. Acta Crystallog. 2001, C57, in press.
    Abstract: Treatment of 9-fluorenyllithium with acetyl chloride produces 9-acetylfluorene (1) and several byproducts. Among them is a compound 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)û]. 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 ¹ electrons of the concave face and the hydroxyl H atom of another molecule adjacent to that face.

  3. 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 submitted May 19 '00, ms No.GD 1104.
    Abstract: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). 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 p electrons in the sp configuration. The existence of (3) exclusively in the sp configuration indicates that in this case the interaction between the tert-butyl group and the fluorene-ring p electrons provides relatively more thermodynamic favorability than the steric interaction between the tert-butyl and 9-methyl groups (ap configuration).

  4. Robinson, P. D., Lutfi, H. G., Hou, Y. and Meyers, C. Y. Unexpected Dipivaloylation of 9-lithiated fluorene. Formation of 9-(2’,2’-dimethyl-1’-pivaloxypropylidine)fluorene. Acta Crystallogr. 2000, C56 submitted May 24 '00, ms No.BK1551.
    Abstract: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’,2’-dimethyl-1’-pivaloxy- propylidine)fluorene C    23H26O2, (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 sp2-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)û at the expense of the corresponding "equivalent" angle C=C-O, which is compressed to 116.46 (19)û.

  5. 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. Biochemical Pharmacology, 2000, submitted May 2X, 2000.
    Abstract: Oxidation of low density lipoproteins (LDL) stimulates atherosclerotic plaque forma- tion. Estrogenic compounds (ELC) from foods 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     phytoestrogens, 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 under- going oxidation were evaluated by using a lag-time assay with continuous monitoring of absorbance at 234 nm. Lag-time 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 thiobarbituric acid reactive substances (TBARS) in LDL, and that GEN and DAI were less effective for inhibiting LDL lipid peroxidation. Finally, electrophoretic 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.

  6. 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.
    Abstract: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.

  7. Yuqing 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, 106-114.
    Abstract: 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.

  8. 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.
    Abstract: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-dimethyl-ethyl)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 ‘ 1b ‘ 4, making 4 the exclusive product from treatment of 1 with HI-CHCl3. In contrast to the other halides, fluoride is a poor nucleophile in displacement 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.

  9. Hou,Y. and Meyers, C. Y., The Surprising Formation of Structurally Distorted ap-9-(o-tert-Butyl- phenyl)-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.
    Abstract: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 subsequent 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 unexpectedly showed that in these ap configurations 9-CH    3 (of 4c) has a greater bulk effect than 9-CH3S (of 4a) in forcing the o-tert-butyl group into the fluorene plane.

  10. Meyers, C. Y., Banz, W. J., Winters, T. A., Hou, Y., Adler, S. R. and Dandliker, W. B. Therapeutic Applications of Estrogenic Carboxylic Acids. Internat'l Patent Application. International Application Number: PCT/US99/13940; Priority Data: 60/090,344, 23 June 1998; International Filing Date: 22 June 1999.
    Abstract: Provided are methods employing estrogenic compounds for: repressing weight gain or reducing weight in male patients; treating or preventing prostate cancer and peri- or post-meno- pausal symptoms; treating estrogen-responsive conditions that no longer respond to treatment with conventional steroidal estrogens; treating or preventing estrogen-responsive uterine cancer, breast cancer, and ovarian follicle atresia; inducing ovulation to increase fertility; oral contraception; treating or preventing diseases or conditions caused or prolonged by free radicals; treating or preventing cardiovascular disease, hyperlipidemia or hypercholesterolemia, and hyperglycemia; improving body fat distribution; and treating or preventing Alzheimer’s disease, osteoporosis, and pattern baldness. Also provided are methods for treating or preventing prostatic diseases including benign prostate hyperplasia and other related conditions, androgen-responsive pathological conditions in males, and methods for male birth control and chemical castration, employing estrogenic carboxylic acids.

  11. Banz, W. J., Winters, T. A., Hou, Y., Adler, S. and Meyers, C. Y., Comparative Effects of the Selective Estrogen Receptor Modulators (-)-, (+)- and (±)-Z-Bisdehydrodoisynolic Acids on Metabolic and Reproductive Parameters in Male and Female Rats. Hormone and Metabolic Research, 1998, 30, 730-736.
    Abstract: Doisynolic acids are non-steroidal estrogenic compounds originally obtained from alkali fusion of estrone and equilenin. Z-bisdehydrodoisynolic acids (Z-BDDA) exhibit a low binding affinity accompanied by a disproportionately high biologic activity. Two experiments were designed to investigate the chronic effects of (+)-, (-)- and (±)-Z-BDDA and 17    b-estradiol (E2) in male and female rats. The (+)-, (-)- and (±) 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 (±)-Z-BDDA had similar estrogenic effects on reproductive organ weight. Surprisingly, (-)-Z-BDDA did not induce the increase in uterine weight observed with (+)- and (±)-Z-BDDA and E2, hence, demonstrating 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.