Karbonil fonksiyonu içeren heterohalkaların atom ekonomik sentezi
Atom economical synthesis of heterocycles having carbonyl function
Yazar: HATİCE NUR KUBİLAY
Danışman: PROF. DR. OLCAY ANAÇ ; DOÇ. DR. GÖKÇE MEREY
İstanbul Teknik Üniversitesi / Lisansüstü Eğitim Enstitüsü / Kimya Ana Bilim Dalı / Kimya Bilim Dalı
Derece: Doktora, 2021
Konu: Kimya = Chemistry
Dizin: Diazo bileşikleri = Diazo compounds ; Karbenoid = Carbenoid ; Katalizörler = Catalysts ; Siklopropan = Cyclopropene

Özet:
Farklı fonksiyonel gruplara sahip heterosiklik bileşiklerin sentezi, uzun yıllardır organik kimya alanında verimli bir araştırma konusu olmuştur. Bu alanda, diazo bileşiklerinin metal katalizörler varlığında reaksiyonlarından yararlanmak oldukça pratik bir yaklaşımdır. Bu yaklaşımla regio-, diastereo- ve enantiyo seçici olarak hedefli heterosiklik yapıların sentezi mümkün olmaktadır. Reaksiyonlarda kullanılan katalizörün metali, ligandının yapısı, diazo bileşiğinde bulunan grupların akseptör/donör özellikleri ve reaksiyon koşulları ürün çeşidini ve dağılımını önemli ölçüde etkilemektedir.
Çalışmada, Mitsunobu reaksiyonu kullanılarak, diazo fonksiyonu bulunduran sekiz farklı N-alkoksi-N-alkilamid türevi sentezlenmiştir. Bu bileşiklerin önemli özelliklerinden biri, yapılarında N-O birimi bulundurmalarıdır çünkü N-O bağı, kolaylıkla kırılarak, diazo reaksiyonu sonrası elde edilen heterosiklik yapıların rahatlıkla farklı türevlere dönüştürülmesine olanak tanımaktadır. Aynı zamanda N-O biriminin kendisi de yapıya ilave elektronik özellikler kazandırmaktadır.
Sentezlenen diazo fonksiyonlu N-alkoksi-N-alkilamid türevleri ile gerçekleştirilen katalitik diazo reaksiyonlarında katalizör olarak CuCl/AgSbF6 karışımı ile Rh2(OAc)4 kullanılmış ve ürün çeşidinin, katalizöre bağlı olarak çarpıcı şekilde değiştiği görülmüştür. Kullanılan çıkış bileşiğindeki alkoksi fonksiyonu üzerinde çift bağ olması durumunda, CuCl/AgSbF6 ile yalnızca siklopropanlaşma reaksiyonu, Rh2(OAc)4 ile de ağırlıklı olarak C-H araya girme reaksiyonu gözlenmiştir.  Bununla birlikte araya girme reaksiyonlarında, amid azotu üzerindeki alkil grubu metil ise oksijene bağlı alkil grubu üzerinden beş üyeli halka; benzil grubu ise, benzil karbonu üzerinden dört üyeli azetidinon halkası elde edilmiştir. Dört üyeli halkaların, beş üyeli halkalara göre daha zor oluştuğu bilinmesine rağmen böyle bir sonuç elde edilmesi dikkat çekicidir. Katalizör olarak Rh2(OAc)4 kullanılan reaksiyonlarda ve amid azotu üzerinde benzil grubu varlığında çok az miktarda da olsa dihidroksi hepta[c]pirol türevleri de elde edilmiştir. Bu türevlerin, aromatik çift bağ üzerinden siklopropanlaşma ve ardından halka genişlemesi ile oluştuğu düşünülmektedir.
Tüm bu reaksiyonlar sonucunda elde edilen bileşikler, literatürde yer almıyor olup ilaç ve malzeme kimyası açısından değerli bileşiklerdir. Yapıdaki N-O birimi, elde edilen ürünlerden kolay bir şekilde farklı türevlerin de elde edilmesine olanak tanımaktadır. Çalışma ile biyolojik aktivite potansiyeli olan bileşiklerin atom-ekonomik (az aşamalı) sentezi gerçekleştirilmiş, uygun yapıda diazo bileşiklerinden yola çıkarak kullanılan katalizöre bağlı olarak hedefli ürünlerin elde edilebileceği  gösterilmiş ve gerçekleştirilen reaksiyonların mekanizmaları irdelenmiştir.

Abstract:
The synthesis of heterocyclic compounds having different functional groups has been a fruitful area of investigation in organic chemistry for several years. In this field, it is a very practical approach to use diazo reactions in the presence of metal catalysts. From this point of view, it is possible to synthesize regio-, diastereo- and enantio-selectively targeted heterocycles. The metal of the catalyst used in the reactions, the structure of the catalyst ligand, the acceptor/donor properties of the functions in the diazo compound and the reaction conditions significantly affect the product type and distribution.
In general, the synthesis of complex heterocycles having the potential for biological activity, is very difficult and costly. A step that will reduce the cost by reducing the synthesis steps is of great importance. In this context, utilizing the reactions of diazocarbonyl compounds with metal catalysts can be seen as an alternative way to reach heterocyclic compounds in a single step and in a short time. These syntheses, which are carried out with fewer steps, are called "atomic economic synthesis".
As versatile carbene precursors, diazocarbonyl compounds allow the synthesis of complex structures via ylide formation, cycloaddition and X-H insertion reactions. Metal salts are required for the activation of the diazo compounds; the most preferred catalysts are copper and rhodium salts, however, there are several catalysts prepared with other transition metals. Electronic and steric property of the functional groups on the diazo compound and catalyst ligands, besides the type of catalyst metal may have drastic effects on the chemo-, regio-, and stereo-selectivity, thus, the product distribution.
In recent years, a great increase has been observed in the number of carbenoid reactions of different structures with various substrates. This is because there is a high rate of chemoselectivity in these reactions, besides, regio-, diastereo- and enantio-selectivities 
The first carbene/carbenoid reactions are cycloadditions to multiple (double/triple) bonds. Moreover, as precursor reactions, insertion reactions (into C-H bond, heteroatom-H bond or aromatic C-H bond), formation of ylides (oxonium ylide, carbonyl ylide, nitrogen and sulfur ylides, etc.) and dipolar additions in the presence of dipoles can be given. For the preference of the reaction route, the type of diazo compound, the used metal complex and the appropriate selection of the substrate structure are of great importance. With the right choices, it is possible to synthesize pharmaceutical compounds and natural compounds with unique stereochemistry and complex structures.
In the study, eight different N-alkoxy-N-alkylamide derivatives with diazo function were synthesized using Mitsunobu reaction. The Mitsunobu reaction is a classical approach to introduce alkoxy function to the compound via the change of the hydroxy function of alcohols by different nucleophiles. One of the important features of the obtained compounds is that they contain N-O moiety which can easily be cleaved to allow the heterocyclic structures to be converted into different useful derivatives. Meanwhile, the N-O moiety itself provides additional electronic properties to the structure.
A mixture of CuCl/AgSbF6 and Rh2(OAc)4 were used in the catalytic diazo reactions of the synthesized N-alkoxy-N-alkylamide derivatives, and it was observed that the product type and distribution changed conspicuously depending on the catalyst. In case of double bonds on the structure, mainly C-H insertion with Rh2(OAc)4 and cyclopropanation with CuCl /AgSbF6 was observed. For the structures without double bond, both catalysts yielded C-H insertion reactions with high yields. In terms of the cyclopropanation reaction, the steric and stereoelectronic position of the Cu(I) carbenoid against the reaction target C=C bond should be evaluated. The structure of the Cu(I) catalyst allows its carbenoid carbon to approach the carbons of the double bond to give a cyclopropanation reaction. However, the carbenoid carbon formed by Rh2(OAc)4 cannot form the steric interaction required for cyclopropanization. Besides, Dewar-Chatt-Duncanson model for alkenes explains that the σ-donor and π-acceptor nature of the used metal on the catalyst affects the activity. While the alkene transfers σ-electrons to the unoccupied d-orbital of the metal, π-backbonding takes place from the metal's d-orbital of the valence shell to the unoccupied π*-orbital of the alkene. This phenomenon facilitates cyclopropanization by lengthening the C=C bond. For Cu(I), σ-electron transfer to the vacant d-orbital is more important than π-backbonding, that is why π-acceptor ligands (e.g. SbF6), reduce π-backbonding to make Cu(I) catalysts more stable for cyclopropanation.
The most important parameter to alter the product distribution in the Rh2(OAc)4 catalyzed reactions is the alkyl group on the amide nitrogen. In the presence of methyl substituent, a five-membered isoxazolidinone ring was obtained via C-H insertion reaction over the alkoxy chain, and a four-membered azetidinone ring was obtained over the benzyl carbon in the presence of benzyl substituent. Four membered ring was preferred in the presence of benzyl group although it is harder to form when compared to five membered rings. 
Another product type observed in the Rh2(OAc)4 catalyzed reactions of the substrates having benzyl is dihydrocyclohepta[c]pyrrole derivatives albeit in very low yield. These derivatives are thought to be formed by cyclopropanization on the aromatic ring followed by ring expansion. In this case, it can be stated that Rh2(OAc)4 catalyst also gives cyclopropanization reaction under the applied reaction conditions.
Heterocyclic compounds form the core structure of many active pharmaceutical ingredients and natural compounds. Heterocyclic compounds are very diverse and classified according to the functional groups on them and their usage areas. In particular, the importance and usage areas of these derivatives in the literature will be mentioned.
As a summary, the heterocycles obtained in this thesis study were mainly isoxazolidinone, azetidinone and cyclopropyl fused oxazinan/oxazepan derivatives. All of these compound classes have area of use as active pharmaceutical ingredients. Proherbicide Clomazon, antibiotic Linezolid, and GABA receptor antagonist Flueggine A are few examples of isoxazolidinones having pharmaceutical use. Isoxazolidinone derivatives containing N-O unit stand out as an important group of compounds due to their area of use and the potential of reaching other useful derivatives by the convertion via N-O bond. Besides, by using these derivatives, it takes few steps to reach β-aminoacids which are valuable compounds to give flexibility to proteins with particular functions.
Like isoxazolidinones, plenty of N-heterocycle fused cyclopropanes are found in a variety of pharmaceuticals such as pheromones and fatty acid metabolites, as well as several drugs some of which show enzyme inhibition, besides antiviral, antifungal, antibacterial, insecticidal and herbicidal activity. Synthesis of strained structures such as cyclopropanes is of great importance because of their stereoelectronic behaviour and eligibility for regio-, diastereo- and enantioselective syntheses. Cyclopropanes form the basis of various pharmaceuticals and are found in a variety of natural products, including pheromones and fatty acid metabolites. There are also examples of cyclopropane adjacent to heterocycles containing nitrogen and/or oxygen. Natural anti-cancer drugs Duocarmycin and CC-1065, adrenaline inhibitor and serotonin reuptake transporter bicifadin and the antibiotics trovafloxacine and indolizomycine are such important cyclopropanes fused to N-heterocycles.
Another product class of this study, azetidinone derivatives, are substructures of β-lactam derivatives which are of the largest class of antibiotics (e.g. peniciline, cephalosporins). β-Lactam derivatives have been in the structure of many antibiotics since the early 1900s. The most common antibiotics among these are penicillin and various cephalosporin derivatives. β-Lactam derivatives inhibit the synthesis of the peptidoglycine compound, which protects the bacterial cell wall by binding to the enzyme, which has an active end as serine amino acid and also called "penicillin binding protein", and shows anti-bacterial activity. It is known that many antibiotics give resistance to bacteria after a certain period of time and therefore there is a constant need for the discovery of new antibiotics. Therefore, it is necessary to synthesize new antibiotics or to create derivatives of used antibiotics. For example, azetidinone derivative Oxamazin is an efficient antibiotic on gram negative bacteria. 
As a result, the compounds obtained from all these reactions are new in the literature and are valuable compounds in terms of pharmaceutical and materials chemistry. In this study, both atom-economic (reduced-step) synthesis of these compounds was carried out and the reaction mechanisms were examined. Finding new methods to synthesize such compounds and shorten the synthesis steps in these methods are of great scientific importance.