First Total Synthesis of the Novel Brominated Polyacetylenic Diol (+) – Diplyne D and Progress Towards the Total Synthesis of (+) - Diplyne E A thesis submitted to the Miami University Honors Program in partial fulfillment of the requirements for University Honors with Distinction by Amanda Lea Jones May, 2005 Oxford, Ohio ii Abstract First Total Synthesis of the Novel Brominated Polyacetylenic Diol (+) – Diplyne D and Progress Towards the Total Synthesis of (+) - Diplyne E by Amanda Lea Jones This thesis describes the methodology and experimental work towards the total synthesis of two novel brominated polyacetylenic diols, diplynes D and E (4-5), isolated from the Philippines sponge Diplastrella sp. The work contained herein represents the first reported synthesis of (+) - diplyne D. These two compounds, along with others isolated from Diplastrella (1-3), inhibited HIV-1 integrase. The synthetic route for diplyne D involved a Cadiot-Chodkiewicz coupling reaction to assemble the right hand portion of the molecule and two Sonogashira coupling reactions to create the diyne and vinyl bromide framework. The stereogenic center was derived from D-mannitol. Once diplyne D had been completed, the focus was shifted to diplyne E. The goal was to create diplyne E through a more convergent synthesis, namely the Sonogashira coupling of the bromine containing enyne to the remaining part of the molecule, which should be easily prepared due to its similarity to diplyne D. While the right hand portion of the molecule has been successfully completed, attempts at the preparation of the enyne fragment have been unsuccessful to date. It is hoped that further research will lead to preparation of the desired product, in which case diplyne E should rapidly follow. iii First Total Synthesis of the Novel Brominated Polyacetylenic Diol (+) – Diplyne D and Progress Towards the Total Synthesis of (+) - Diplyne E By Amanda Lea Jones Approved by: _______________________, Advisor Dr. Benjamin W. Gung _______________________, Reader Dr. Michael W. Crowder _______________________, Reader Mr. Craig R. Gibeau Accepted by: _______________________, Director University Honors Program iv Acknowledgments I would like to thank my advisor, Dr. Benjamin Gung, for his knowledge, guidance, and support throughout the duration of this project as well as my entire undergraduate research career at Miami University. In addition, I would like to thank each member of the Gung research group I have come to know over the last two years for their help and patience. Thanks also to the Arnold and Mabel Beckman Foundation for financially supporting this project. Last but not least, thanks to all of my family and friends for always believing in me. v Table of Contents Page List of Abbreviations vii List of Figures viii List of Schemes ix List of Structures x Chapter 1: Introduction 1 Chapter 2: The Total Synthesis of (+) – Diplyne D 2.1 Introduction 7 2.2 Results and Discussion 8 2.3 Conclusion 10 2.4 Experimental 11 Chapter 3: Progress Towards the Total Synthesis of (+) - Diplyne E 3.1 Introduction 19 3.2 Results and Discussion 21 3.3 Experimental 25 Chapter 4: References 31 Chapter 5: Spectra for Selected Compounds 34 vi List of Abbreviations DMSO dimethyl sulfoxide Et ethyl HRMS high resolution mass spectrometry i-Pr isopropyl IR infrared Me methyl NaHMDS sodium bis(trimethylsilyl)amide NBS N - bromosuccinimide NMR nuclear magnetic resonance ppm parts per million rt room temperature sat. saturated TBAF tetrabutylammonium fluoride TBDPS tert-butyldiphenylsilyl TEA triethylamine THF tetrahydrofuran TIPS triisopropylsilyl TMS trimethylsilyl UV ultraviolet vii List of Figures Figure 1 (-) – Minquartynoic acid Figure 2 Diplynes A-E isolated from Diplastrella sp. Figure 3 A brominated polyacetylenic acid isolated from Xestospongia muta Figure 4 Retrosynthetic analysis of diplyne D 4 Figure 5 Retrosynthetic analysis of (+) – diplyne E 5 Figure 6 Sonogashira coupling reactions of vinyl halides with silyl acetylenes viii List of Schemes Scheme 1 Synthesis of (+) – diplyne D Scheme 2 Synthesis of advanced intermediate 19 Scheme 3 Synthetic attempts toward enyne 20 ix List of Structures Br 1 OH OH Diplyne A Br OH 2 OH Diplyne B Br OH 3 OH Diplyne C Br OH 4 OH Diplyne D x Br OH 5 OH Diplyne E O Br O 6 4-Bromoethynyl-2,2-dimethyl-[1,3]dioxolane O O 7 4-Deca-1,3,9-triynyl-2,2-dimethyl-[1,3]dioxolane O O O 8 O Cadiot Chodkiewicz coupling of 6 to both ends of 1,7-octadiyne Br O O 9 4-(10-Bromo-deca-1,3,9-triynyl)-dimethyl-[1,3]dioxolane xi TIPS O O 10 [12-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-dodeca-1,3,9,11-tetraynyl]-triisopropyl-silane TIPS OH 11 OH 14-Triisopropylsilanyl-tetradeca-3,5,11,13-tetrayne-1,2-diol OH OH 12 Tetradeca-3,5,11,13-tetrayne-1,2-diol H Br 13 1-Bromo-but-1-ene-3-yne I 14 H 1-Iodo-oct-1-ene-7-yne HO 15 6-Heptyn-1-ol xii HO O O 16 9-(2,2-dimethyl-[1,3]dioxolan-4-yl)-nona-6,8-diyne-1-ol O O O 17 9-(2,2-dimethyl-[1,3]dioxolan-4-yl)-nona-6,8-diynal I O 18 O 4-(10-Iodo-dec-9-ene-1,3-diynyl)-2,2-dimethyl-[1,3]-dioxolane I OH OH 19 12-Iodo-dodec-11-ene-3,5-diyne-1,2-diol TIPS Br 20 (4-Bromo-but-3-ene-1-ynyl)-trisopropylsilane xiii TIPS TIPS 21 1,4-Bis-trisopropylsilanyli-buta-1,3-diyne xiv Chapter 1 Introduction 1 The total synthesis of natural products is a branch of synthetic organic chemistry that stems from the desire to prepare biologically active molecules that have been isolated from natural sources. The quest for new treatments and cures for debilitating or fatal diseases has promoted the rapid expansion of this field. In addition, it is becoming ever more important to have a means by which natural products can be prepared efficiently and economically, since most natural sources, such as plants or marine sponges, are limited resources and may produce only small amounts of each compound. One particular group of compounds that has been receiving increased interest over the past few years are polyacetylenes. One example of such is (-) – minquartynoic acid, an anti-cancer, anti-HIV natural product synthesized recently1 (see Figure 1). Figure 1 HO Me CO2H (-) – Minquartynoic acid Not only do these types of molecules occur often in nature, but many show potent biological activity and provide challenging architectures that attract the interest of organic chemists. The desire to synthesize targets that satisfy these properties was the main basis for this research and led to interest in five novel brominated polyacetylenic diols, diplynes A-E (1-5), shown in Figure 2. 2 Figure 2 Br 1 OH OH Br OH 2 OH Br OH 3 OH Br OH 4 OH Br OH 5 OH Diplynes A-E isolated from Diplastrella sp. Each of these compounds was isolated from the Philippines sponge Diplastrella sp. and showed HIV-1 integrase inhibitory activity in bioassay-guided fractionation.2 The HIV virus, as is well known, leads to AIDS and is becoming more prevalent in today’s society. HIV-1 integrase is an enzyme responsible for integrating viral DNA into the DNA of a healthy cell, thereby causing the healthy cell to now create viral proteins.3 The discovery of effective treatments is biomedically important, and the potential anti-HIV properties of these brominated polyacetylenic diols is therefore a main reason for synthesizing this group of natural products. 3 In addition to the polyacetylenic portions, there are other structural features of the diplyne compounds worth noting. Each has a characteristic diol end group and one stereogenic center at C2. Due to the small amount of each compound isolated, the absolute configuration of this stereocenter was not determined in the initial report.2 However, (+) - diplyne A was recently synthesized and found to have an (S) configuration.4 This led to the conclusion that the naturally occurring (-) - diplyne A must have an (R) configuration at C2.4 Due to the structural similarity between 1-5, the structures of the other naturally occurring diplynes have been tentatively assigned (R) as well.4 Another characteristic of compounds 1-5 is the vinyl bromide group. More and more brominated compounds are reported each year as coming from marine sources,2 and many of these compounds exhibit favorable biological activities. For example, brominated polyacetylenic acids isolated from Xestospongia muta5 (Figure 3) have been shown to inhibit HIV protease.5 Figure 3 Br COOH Brominated polyacetylenic acid isolated from Xestospongia muta This compound shown in Figure 3 has striking similarities to the diplyne family of compounds. However, 1-5 are the first brominated polyacetylenic diols that have been reported.2 4 This thesis describes the methodology and experimental work concerning the first total synthesis of (+) - diplyne D 4 and synthetic attempts toward a member of the same family of compounds, (+) - diplyne E 5. These two compounds, along with others isolated from Diplastrella (1-3), showed activity in the HIV-1 integrase inhibition assay. Due to the prevalence of the HIV virus in today’s society, there is high demand for effective treatment, which gives a basis for pursuing these two compounds. 5 Chapter 2 The Total Synthesis of (+) - Diplyne D 6 2.1 Introduction Diplyne D 4 is a member of a family of five novel brominated polyacetylenic diols isolated from the marine sponge Diplastrella sp., which showed HIV-1 integrase inhibitory activity when subjected to a bioassay-guided fractionation.2 Based on previous work done by other members of my research group1, 6-7 involving the synthesis of polyacetylenes, a retrosynthetic analysis was developed (see Figure 4).