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Solid-Phase Combinatorial Synthesis: Wittig Reaction for C=C Formation in Tamoxifen Derivatives David Yu-Chung Lee

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Solid-Phase Combinatorial Synthesis: Wittig Reaction for C=C Formation in Tamoxifen Derivatives David Yu-Chung Lee Rochester Institute of Technology RIT Scholar Works Theses Thesis/Dissertation Collections 2003 Solid-phase combinatorial synthesis: Wittig reaction for C=C formation in Tamoxifen derivatives David Yu-Chung Lee Follow this and additional works at: http://scholarworks.rit.edu/theses Recommended Citation Lee, David Yu-Chung, "Solid-phase combinatorial synthesis: Wittig reaction for C=C formation in Tamoxifen derivatives" (2003). Thesis. Rochester Institute of Technology. Accessed from This Thesis is brought to you for free and open access by the Thesis/Dissertation Collections at RIT Scholar Works. It has been accepted for inclusion in Theses by an authorized administrator of RIT Scholar Works. For more information, please contact [email protected]. Solid-Phase Combinatorial Synthesis: Wittig Reaction for C=C Formation in Tamoxifen Derivatives David Yu-Chung Lee June 2003 A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in chemistry Approved: ___K_a----'y~T_u_r_n_e_r __ Thesis Advisor T. C. Morrill Department Head Department of Chemistry Rochester Institute of Technology Rochester, NY 14623-5603 Copyright Release Fonn Solid-Phase Combinatorial Synthesis: Wittig Reaction for C=C Formation in Tamoxifen Derivatives I, David Yu-Chung Lee, hereby grant permission to the Wallace Memorial Library, of RIT, to reproduce my thesis in whole or in part. Any use will not be for commercial use or profit. Signature: __________Daniel Y. Lee _ Date: 'l/ { / ~.3 ; , Table of Contents Abstract i List of Tables ii List of Figures hi List of Schemes iv Chapter 1. Introduction 1 1.1 Tamoxifen 1 1.2 The Concept of Combinatorial Chemistry 6 1.3 Methods in Generating Combinatorial Libraries 7 1.4 Solid-Phase Synthesis 9 1.5 Resin: The Solid Support 10 Chapter 2. Purpose of Research 15 Chapter 3. Materials and Methods 21 3.1 Solid-Phase Synthesis of Stilbene Derivatives 21 3.1.1. Procedure No. 1 Solid-Phase Synthesis of Stilbene Derivatives Based on Procedures by Bernard and Ford (Scheme VII) and Argonaut (Table I, column 1) 24 3.1.2. Procedure No.2 Optimized Version of Procedure No. 1 24 3.1.3. Procedure No.3 Based on the Procedure Provided by NovaBiochem (Table I, column 2) 25 3.2 Synthesis of Tamoxifen Derivatives 25 3.2. 1 Procedure No. 4 Solution-Phase Triphenylethylene Synthesis 25 3.2.2 Procedure No. 5 Solid-Phase Synthesis of Tamoxifen Derivatives (Using Triphenylethylene Synthesis as an Example) 26 3.3 Product Analysis 27 Chapter 4. Results and Discussion 30 4.1 The Initial Stilbene Synthesis 30 4.2 Optimization: From Procedure No. 1 to No.2 32 4.3 The First Stilbene Library 35 4.3.1 Reactivities of the Benzyl Halides 35 4.3.1.1 Special Study for 4-Methoxy Benzyl Chloride 35 4.3.1.2 Electron Donating/Withdrawing Effects 36 4.3.2 The Effects of Functional Groups on Aldehydes 38 4.4 The Second Stilbene Library 40 4.4.1. Closer Examination ofArgonaut's Data 40 4.4.2. The NovaBiochem Resin 42 4.4.3. Data Interpretation 45 4.5 Liquid-Phase Synthesis of Triphenylethylene 45 4.6 Solid-Phase Synthesis ofTamoxifen Derivatives 49 Chapter 5. Conclusion and Suggestions for Future Study 53 Appendix Gas Chromatograms of the Second Stilbene Library 55 Abstract Tamoxifen has a backbone structure of triphenylethylene and is a drug that has been used for over 20 years to treat patients with breast cancer. It has been discussed in the literature that the C=C formation would be the desired synthetic approach because of its flexibility in the introduction of suitable functional groups using readily available reagents. Solid-phase combinatorial approach is adopted for the purpose of product diversity and simplicity in product analysis. This research focused on optimization of each reaction step in the Wittig mechanism to overcome low yield caused by employing solid-state chemistry and the steric hindrance of C=C formation. It has been discovered that commercially available polystyrene-triphenylphosphine resins require extreme reaction conditions and may not be applicable for the pharmaceutical industry. List of Tables Table I. Commercially Available Crosslinked Polystyrene-Triphenylphosphine Resins Used in This Research 23 Table II. GCMS Conditions 29 Table III. Adjustments from Procedure No. 1 to Procedure No.2 33 Table IV. Comparison of Triphenylphosphonium Salt Formations from Benzyl Halides with Different Functional Groups 38 Table V. Results Published by Argonaut 42 List of Figures Figure 1. A Simple Illustration of Parallel Synthesis 7 Figure 2. An example of generating 1,000 compounds from ten reagents and three reaction steps using (a) parallel synthesis and (b) split-pool synthesis 8 Figure 3. General Procedure of Solid-Phase Synthesis. Reprinted from Hinks and Swali(2002) 10 Figure 4. Functionalization of a Crosslinked Polystyrene Resin 13 Figure 5. Yields of a Five-by-Five Library of Tamoxifen Derivatives Synthesized by Brown and Armstrong 18 Figure 6 . Structures of Reagents and Products in the Initial Stilbene Synthesis 31 Figure 7. Structures and Percent Yields of the First Stilbene Library 34 Figure 8. Formation of a Triphenylphosphonium Salt via Nucleophilic Substitution Reaction between a Triphenylphosphine and a Benzyl Halide with a Functional Group 37 Figure 9. Mechanism of the Last Step in the Wittig Reaction, (a) Formation of an Oxaphosphetane. (b) Formation of a Betaine 40 Figure 10. Structures, Percent Yields, and cis : trans ratios of the Second Stilbene Library 44 Figure 11. Gas Chromatogram of Liquid-Phase Triphenylethylene Synthesis 47 Figure 12. Mass Spectra of (a) the Peak with Retention Time = 15.32 min from Figure 11 (b) Triphenylethylene (c) Triphenylphosphine 48 Figure 13. Summary of Four Solid-Phase Reactions for Tamoxifen Derivative Synthesis 49 Figure 14. Gas Chromatogram of Solid-Phase Synthesized Triphenylethylene 51 Figure 15. Mass Spectra of (a) Solid-Phase Synthesized Triphenylethylene and (b) Standard Triphenylethylene (from GCMS Internal Library) 52 List of Schemes Scheme I. An Example of Non-Stereospecific Synthesis of Tamoxifen 4 Scheme II. An Example of Stereospecific Synthesis oftrans-Tamoxifen 5 Scheme III. Synthesis of Tamoxifen Derivatives via the McMurry Reaction 16 Scheme IV. Solid-Phase Synthesis of Tamoxifen Derivatives from Five Alkynes and Five Aryl Halides via Resin Capture 16 Scheme V Proposed Solid-Phase Wittig Reaction for Tamoxifen Synthesis 18 Scheme VI. Schlosser Modification of the Wittig Reaction 20 Scheme VII. Bernard and Ford's Procedure for Solid-Phase Wittig Synthesis of Stilbene. 22 Chapter 1. Introduction 1.1 Tamoxifen Tamoxifen (Nolvadex) is a drug that has been used for over 20 years to treat patients with advanced breast cancer. It is used as adjuvant, or additional cancer.1 therapy following primary treatment for early stage breast Tamoxifen is classified as an antiestrogen. An antiestrogen or estrogen blocker works by blocking estrogen in breast tissue. While estrogen may not actually cause breast cancer, it may stimulate its growth, feeding the cancer. With estrogen blocked, the cancer cells that need it may not grow at all. In other words, antiestrogens may keep cancer from developing in the breast2. Research has shown that when Tamoxifen is used as adjuvant therapy for early stage breast cancer, it reduces the risk of recurrence of the original cancer and also reduces the risk of developing new cancers in the other breast. Based on these findings, the National Cancer Institute (NCI) funded a large research study to determine the usefulness of Tamoxifen in preventing breast disease.1 cancer in women who have an increased risk of developing the This study, known as the Breast Cancer Prevention Trial (BCPT), involved 13,000 premenopausal and postmenopausal women at high risk of breast cancer. Results of this trial were announced on April 6, 1998, and published in the 1 Tamoxifen: Questions and Answers. National Cancer Institute. http://cis.nci.nih.gOv/fact/7 16.htm (accessed April 2003) 2 NOLVADEX (tamoxifen citrate) Home Page, http://www.nolvadex.com/consumer/home.asp (accessed April 2003) Journal of the National Cancer Institute five months later on Sept. 16. In the BCPT, half the women took Tamoxifen and half took a placebo (an inactive pill that looked like Tamoxifen). Participants taking Tamoxifen also had fewer fractures of the hip, wrist, and spine than women taking the placebo. However, the drug increased the women's chances of developing four potentially life-threatening health problems: endometrial cancer (cancer of the lining of the uterus), deep vein thrombosis (blood clots in large veins), pulmonary embolism (blood clot in the lung), and possibly stroke. The U.S. Food and Drug Administration (FDA) approved the use of Tamoxifen to reduce the incidence of breast cancer in women at increased risk of the disease in October 1998. / /raws-Tarnoxifen *This isomer is also "Z" assigned in the \ / literature, which does sometimes cause confusion. Only cisltrans designations are used in this thesis. Tamoxifen has a backbone structure of triphenylethylene (see above). Only the trans isomer is an antiestrogen and active in the treatment of breast Raloxifene Under Across North America. The Cancer Clinic Study of Tamoxifen and (STAR) Way Hereditary (accessed April at Duke Comprehensive Cancer Center, http://cancer.duke.edu/hcc/siar.nsp 2003) uses.4 cancer. Its cis isomer has no clinical Several papers have been published regarding the synthesis of Tamoxifen5'6,7,89, from which two exemplary synthesis, stereospecific and non-stereospecific, are shown in I5 II6 Scheme and Scheme respectively. Magdalen College Oxford. Wilson C Tamoxifen (Tamoxifen Citrate). ar..Mk/mom/Tamoxifin/Tamoxifin.htm (accessed April httr//..'m, nhPm n 2003) Synthesis of the E and Z Isomers of the Antiestrogen Tamoxifen and Its Robertson D. W.; Katzenellenbogen, J. A. Tritium-Labeled Form. J. Org. Chem. 1982. 47. 2387-2393 Metabolite Hydroxytamoxifen, in Stereospecific Synthesis of (Z) Tamoxifen via Carbometalation ofAlkynylsilanes.
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