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Lythgoe Olefination Method Univerzita Palackého v Olomouci Přírodovědecká fakulta Sulfur-based methodologies in the context of olefination and diversity-oriented synthetic methods RNDr. Jiří Pospíšil, Ph.D. Habilitační práce Vědní obor: Organická chemie Olomouc 2017 Prohlašuji, že předloženou práci jsem vypracoval samostatně s využitím informačních zdrojů, které jsou citovány. V Olomouci dne 30.08.2017 RNDr. Jiří Pospíšil, Ph.D. HABILITAČNÍ PRÁCE | RNDr. Jiří Pospíšil, Ph.D.|PAGE 2 In memory of my Ph.D. supervisor professor István E. Markó, who passed away prematurely this summer… Acknowledgement At this point I would like to thanks to my wife, Corinne, for her presence, encouragement and support, because without that I would not be able to reach this particular point – writing my Habilitation Theses. Additionally I have decided to thanks to all ‘Blood’, ‘Scientific’ and ‘Friend’ family members that have had a key influence to my life. To do so I have made a list of key “phrases” that had and some still has influence on my life. “Good work praises itself, so do not expect me to ever praise you…” (Jiří Pospíšil, my father). “So Jiří you’re going to work on 1.3-dipolar cycloadditions ...” (prof. Milan Potáček, when he accepted me as a 1st year university student in his group). “Soooo, what’s new?” (prof. Alois Fürstner and prof. Milan Potáček, about once per week when passing by through the lab). ”How is doing my ambruticin?” (prof. István E. Markó, asking about the progress in the total synthesis) “What a Mickey mouse molecule” (prof. Alois Fürstner, commenting the next failed approach in aspecyclide C synthesis). “Some people are lucky, some less. Just keep fighting. It will turn.” (prof. Samir Zard, while discussing chemistry and other things with him). “Remember, your publications will never be perfect. Just publish!!” (prof. Philippe Henne, o.p., during the discussion we had in summer 2016). “Can we go with you to the lab?” and “Can I have also my lab when I will be older to play with molecules?” (my kids – those who are already able to talk ). HABILITAČNÍ PRÁCE | RNDr. Jiří Pospíšil, Ph.D.|PAGE 3 Table of contents 1. Introduction ..................................................................................................................... 6 2. Olefination reactions in organic chemistry .................................................................... 10 2.1 Sulfur-based olefination methods .................................................................................. 11 2.1.1 Julia-Lythgoe olefination method .................................................................................. 11 2.1.2 Julia-Kocienski olefination method ................................................................................ 16 2.2 Our contribution to the field of sulfur-based olefination methods ............................... 22 2.2.1 Sulfoxide version of Julia-Lythgoe olefination ............................................................... 22 2.2.2 Sulfoxide-modified Julia-Lythgoe olefination reaction – applications in natural product synthesis ......................................................................................................................... 28 2.2.3 Entering the world of the Julia-Kocienski olefination .................................................... 30 2.2.4 Julia-Kocienski olefination – enhancing the (E)-selectivity ............................................ 33 2.2.5 Julia-Kocienski olefination – enhancing the (Z)-selectivity ............................................ 35 2.2.6 New insights into the reaction mechanism of the Julia-Kocienski olefination reaction 36 2.3 Microwave promoted Wittig reaction in the plant secondary metabolite synthesis .... 39 3. Diversity-Oriented synthesis .......................................................................................... 41 3.1 Introduction ................................................................................................................... 41 3.1.1 Ideal functionally diverse library .................................................................................... 41 3.1.2 Designing the library ...................................................................................................... 41 3.1.3 Sources of small molecules ............................................................................................ 42 3.1.4 DOS approaches focused on the generation of diverse libraries ................................... 43 3.1.4.1 The reagent-based approach .................................................................................... 43 3.1.4.2 The substrate-based approach .................................................................................. 43 3.1.4.3 The Build/Couple/Pair strategy (B/C/P) .................................................................... 44 3.2 Our design of synthetic strategies suitable for structural and functional complexity driven DOS ...................................................................................................................... 45 3.2.1 Build and Couple phase – synthesis of Parent Molecules 3-10 ..................................... 47 3.2.2 Pair phase - reagent-driven DOS synthesis .................................................................... 49 3.2.2.1 Target: ketones (3-25) and esters (3-26) ................................................................... 49 3.2.2.2 Target: selective synthesis of (E) and (Z)-olefins 3-27 ............................................... 54 3.2.2.3 Target: alkyne 3-28 synthesis .................................................................................... 57 3.2.3 One-pot Couple/Pair phase – towards the new C-C coupling reaction ......................... 59 3.2.4 Divergence in B/C/P strategy - use of 3-10 as C-nucleophiles in Mitsunobu reaction .. 60 4. Conclusions and perspectives ........................................................................................ 62 5. Literature ........................................................................................................................ 63 6. Appendix……………………………………………………………………………………………………………….. 66 HABILITAČNÍ PRÁCE | RNDr. Jiří Pospíšil, Ph.D.|PAGE 4 HABILITAČNÍ PRÁCE | RNDr. Jiří Pospíšil, Ph.D.|PAGE 5 1. Introduction Organic synthesis. A term that according to Wikipedia encyclopedia describes organic synthesis as ‘a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions’.1 The definition so precise (just one sentence) and, at the same time, so inaccurate. The field of organic synthesis includes so many well-defined subfields that are not obviously included within the above-mentioned encyclopedia definition. One can easily imagine that the development of new synthetic methodologies is a key part of the domain. However, additional subfields such as organic reaction mechanism determination, synthesis of new materials, shedding light into biochemical transformations, or studying metabolic pathways within living organisms are most of the time out of consideration when the term is used. As a consequence, when one introduces himself/herself as an organic synthetic chemist, you never know if this person devotes his/hers life to the synthesis of awkwardly complex natural or nature-inspired compounds, or if they studied the mechanism of a specific enzymatic transformation. As shown above, the field of interest of organic synthesis is very broad and includes many different subfields. At first glance, most of them do not have much in common linking them together. However, there is one very important constant through-out the field of organic synthesis as an imaginary tine red line – the creativity. Indeed, creativity is the aspect to which organic synthetic chemists devote their lives to, directly – compounds generating activities, or indirectly – studying how compounds themselves are created. One such field is focused on bioactive small molecules. Small molecules were, are, and will be in the collimator of an organic chemist’s interest. In the beginning, the interest was focused on the small molecules already present in living systems. The quest focused on the small molecules presented throughout living organisms that have virtually no reason for being there. In the end, the curiosity driven research resulted in the discovery of glucose (A. Marggraf, 1747), amino acids (1st half of the 19th century), vitamins (1st half of the 20th century), hormones (1st half of the 20th century), neurotransmitters (1st half of the 20th century), to name a few. From the 2nd half of the 20th century, small molecules slowly but progressively started to occupy the place of life processes probes. First newly discovered small molecules with unknown functions in the organism were synthetically modified. The behavior and the destiny of such small molecules within the living cells then allowed us to study and to understand various biological processes. To give a few examples, such an approach was adopted during the study of ion channels and neurotransmissions,2 protein kinases and signal transduction,3 or when colchicine and cytochalasins were used to illuminate the molecular components of the cytoskeleton4 (Figure 1). HABILITAČNÍ PRÁCE | RNDr. Jiří Pospíšil, Ph.D.|PAGE 6 H Probes to study ion Probes to study cytoskeleton Protein kinase C channels and activator neurotransmitions O H H 3CO OCH3 H H3CO HO O HO OH O OH H3CO HO NH2 Ingenol mebutate O Colchicine Dopamine NH O Protein kinase C HO inhibitor HO CH3 OH
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