ABSTRACT ADDITION OF CARBONYL COMPOUNDS TO THE CYCLIC OLEFINS: SYNTHESIS OF CYCLITOLS Altun, Yasemin M.S., Department of Chemistry Supervisor: Prof. Dr. Metin Balci October 2008, 160 pages Cyclitols have attracted a great deal of attention in recent years owing to biological activities exhibited by them and also their usefulness in the synthesis of other natural products and pharmaceuticals. Carbasugars are also a derivative of cyclitols and they are cyclic monosaccharide analogues which posses &amp / #8211 / CH2OH group in their structure. In this study, novel synthetic strategies leading to cyclitol derivatives were investigated and the synthesis of tetraol (72) and pentaol (73) derivatives containing &amp / #8211 / CH2OH group were achieved successfully. Moreover, by the use of manganese(III) acetate oxidation reactions having considerable synthetic utilities in organic chemistry we developed new synthetic methodologies for the cyclitol derivatives. 1,3- and 1,4-Cyclohexadiene (71 and 10) were synthesized from easily available starting materials in order to be used as key compounds. The use of manganese(III) acetate oxidation reaction provides the creation of &amp / #8211 / CH2OH group and one of the hydroxyl groups and the remaining hydroxyl groups were introduced into the key compounds by the use of singlet oxygen reaction. As a result of this, we had considerable advance in the synthesis of cyclitol derivatives.

Phosphorous containing small cycles are very important building blocks in organic and medicinal chemistry. Many of their derivatives, especially cyclopropyl- and 1,2- epoxypropylphosphonates, have attracted great attention due to the broad spectrum of their biological properties including antiviral, anticancer, antibiotic, antibacterial, pesticidal, insecticidal and enzyme inhibitory activities. The Darzens condensation is one of the most potential methodologies for the preperation of &amp / #945 / ,&amp / #946 / -epoxy carbonyl compounds with complete control of two stereogenic centers. The Darzens condensation reaction represents one of the classical C-C and C-O bond-forming processes. In the first part of the thesis, reactions of a broad range of acyl phosphonates with substituted &amp / #945 / -bromo acetophenones at room temperature in the presence of different bases were examined in order to illustrate the reaction and the substituent effect on the reaction. The reaction affords two diastereomeric epoxy phosphonates in good yields and high diastereoselectivities. In the second part of the thesis, it is shown that a variety of radicals can be generated from the substituted aryl boronic acids with Mn(OAc)3. In the presence of acetonitrile, these radicals were added to carbon of acetonitrile to afford the corresponding ketones after hydrolysis of the formed imine with moderate to good yields.

The one electron oxidant Mn(OAc)3 has been used for years for the oxidative addition of 1,3-dicarbonyls to alkenes to give dihydrofuranes. Since cycloheptatriene is in equilibrium with its valance isomer norcaradiene, it will be interesting to study the reaction of CHT derivatives with Mn(OAc)3 in the presence of 1,3-dicarbonyls. In our research, we have observed that unsubstituted cycloheptatriene gave CHT based products. However, when electron withdrawing -CN group was attached to C-7 position of CHT we obtained norcaradiene based products. We have also observed that there exist an equilibrium between [3+2] addition products through 1,5-hydride shift. In addition, we obtained dihydrofurane derivatives in the presence of Mn(OAc)3 from compounds which have already formed C-C bond between 1,3- dicarbonyl and alkene. Formation of dihydrofurane derivatives from these compounds brought up two questions / whether cyclization is going over oxygen atom or not and whether reaction involves a cyclopropane intermediate or not. Despite all efforts, we could not manage to synthesize the required material for the investigation of these questions.

Chiral cyclic alkenols with hydroxymethyl functionality are important structural units in many biologically active natural compouds such as prostaglandins, sesquiterpene antiviral agents, pentenomycins, xanthocidin, sarkomycin, etc. 1,3-cycloalkanediones are converted into bicyclic polyoxo derivatives with formaldehyde and trioxane in the presence of Lewis acid. Selective oxidation of the bicyclic compounds by using manganese(III)acetate followed by enzyme-catalyzed kinetic resolution afforded chiral bicyclic hydroxy ketones. Reduction of carbonyl group and cleavage of the ether functionality furnished the desired chiral cycloalkanols with hydroxymethyl group. This study is a model for the synthesis of these type of compounds.

Chiral hydroxylated cyclopentane derivatives are important precursors for biologically active compounds. Synthesis of these types of compounds in optically pure form found increased interest in pharmaceutical chemistry. 2-ethyl-cyclopentane-1.3-dione was acetoxylated using manganese III acetate at preferred positions. Enzyme catalyzed enantioselective hydrolysis or enantioselective acetoxylation of hydrolyzed acetoxy derivatives gives the corresponding hydroxylated diketones in optically pure form.

Chiral hydroxylated cyclopentane derivatives are important structural units in many biologically active compounds and are also important synthons for the asymmetric synthesis of natural products. Synthesis of these types of compounds in optically pure form found increased interest in pharmaceutical chemistry. For this purpose 5-acetoxy-3-methyl-2-methoxy-2-cyclopentene-1-one and 5-acetoxy-3-ethyl-2-methoxy-2-cyclopentene-1-one were acetoxylated using manganese (III) acetate at a&rsquo / positions. Enzyme catalyzed enantioselective hydrolysis of hydrolyzed acetoxy derivatives gives the corresponding hydroxylated diketones in optically pure form.

Manganese(III) acetate mediated radical cyclisations provide a mild and powerful tool in the construction of complex bicyclic systems. This thesis focuses on the formation of a number of alkenyl substituted [3.3.0]-bicyclic γ-lactones utilising a manganese(III) acetate/copper(II) triflate induced radical cyclisation. The methodology was then applied to a short catalytic and enantioselective synthesis of (+)-aphanamol I and related natural products. Chapter 1 presents a summary of the theories and methodology which will be utilised in this work. In particular, a key focus will revolve around oxidative radical cyclisations and how manganese(III) acetate has become a vital oxidant in such areas. Chapter 2 details a catalytic and asymmetric total synthesis of (+)-aphanamol I. Following an overview of the natural product and its previous total synthesis, a racemic and asymmetric total synthesis is presented which utilises a manganese(III) acetate mediated radical cyclisation and a Claisen ring expansion as key steps. Chapter 3 reports the synthesis and subsequent cyclisation of a wide range of dienyl malonate substrates. Variation of the γ-substituent is first explored, demonstrating the effect that substituent size has on the diastereoselectivity of the cyclisation. Following this, the synthesis of [2.3.0]-,[4.3.0]- and [5.3.0]- bicyclic γ-lactones are investigated. Chapter 4 describes studies towards the total synthesis of a dolabellane natural product. Investigations into substrate synthesis which can be used in a RCM will be presented. Full experimental details and spectral data, with select NMR spectra are also provided.

The first part of the thesis presents the reinvestigation of the synthetic and mechanistic aspects of manganese (III) acetate mediated reactions. The main concern about this subject was to perform a &cent / - acetoxylation reactions of enones and saturated systems in shorter reactions times and higher yields than the ones known in literature reproducibly. Although successful a &cent / -acetoxylation of a great variety of substrates have been reported so far, there are some problems associated with the use of Mn(OAc)3. Considering that there are not many simple methods for the direct acetoxylation of enones, optimization of Mn(OAc)3 mediated a &cent / -acetoxylation of enones and reaching its maximum potential has a great importance from a synthetic and economical point of view. In the second part of the thesis, 1,2,4-trisubstituted pyrrole derivatives were the target molecules to be synthesized. Although there are quite a number of methods available for the synthesis of pyrroles, most of them involve multistep synthetic operations which lower the overall yield. There are limited reports on the preparation of the enantiomers of pyrrole derivatives having 1-N directly linked to the stereogenic center. Thus, developing a new synthetic method for the efficient preparation of polysubstituted pyrroles without racemization still remains an attractive goal.

Additions of carbon-centered radicals to alkenes are useful method for cyclic compounds formation. Manganese(III)-based oxidative free-radical cyclizations, where the radicals are generated and terminated oxidatively, are established as efficient methods for the construction of cyclic molecule. Treatment of a mixture of dimedone, Mn(OAc)3, and Cu(OAc)2 in glacial acetic acid with homobenzonorbornadiene (80) (4h at 50 &amp / #61616 / C) gave furan derivative (107), dihydrofuran adduct (108), in addition to rearranged product (109) as a major product. The reaction run under the same reaction conditions without using Cu(II)acetate for 8h afforded dihydrofuran adduct (108) along with dihydrofuran (110), where no rearranged products could be formed. On the other hand, reflux of alkene 80 with a mixture of acetylacetone, Mn(OAc)3, and Cu(OAc)2 in glacial acetic acid (3h at 50 &amp / #61616 / C) gave oxidative product (131) and rearranged product (132) (major). The reaction run under the same reaction conditions without using Cu(II)acetate for 7h produced, in addition to the oxidative product 131, a dihydrofuran derivative (133). In a second system, we examined the oxidation of benzobarrelene 82 with Mn(OAc)3, and Cu(OAc)2 in glacial acetic acid (1h at 50 &amp / #61616 / C) in presence of dimedone resulted in the formation of five different products rearranged products (148, 149) and a dihydrofuran (109), besides, a mixture containing two major rearranged isomers (150/151). The same reaction was carried out under the same conditions in absence of Cu(II) for 9h and gave the isomeric mixture 150/151 exclusively, and the yield was reduced. The oxidative cyclization of acetylacetone with alkene 82 for 3h at 50 &amp / #61616 / C, afforded in addition to the dihydrofuran (132), two rearranged products (169, 170) and a mixture consisting of two isomers (171/ 172). The isomeric mixture was converted to one product by treatment with methanolic ammonia providing hydroxyl derivative which was oxidized by MnO2 to afford product 174 in a good yield. Additionally, we investigated the behavior of nitrogen bridge in the bicyclic system on the course of the reaction. Oxidation of N-carbethoxy-7-aza-2,3-benzonorbornadiene 83 with dimedone in the presence of Cu(OAc)2 as well as in its absence in glacial acetic acid (2h at 50 &amp / #61616 / C), rearranged product (189) was obtained as the sole product. Regarding the reaction of aza-derivative 83 with acetylacetone in the presence of Cu(OAc)2 (18 h at 50 &amp / #61616 / C), rearranged product 195 was resulted as sole product. The reaction of 83 was also run with out Cu(OAc)2 for 22h and gave the rearranged product 195.

The objective of this presented study was to synthesize optically active compounds considered to be key intermediates in the synthesis of Oseltamivir (Tamiflu) by performing chemical and biotechnological methods. Thereof, the carboethoxy cyclohexenone skeleton first was synthesized utilizing easily available substances. The synthesis of alpha-hydroxy ketones in enantiomerically pure form offers a great importance in the synthesis of biologically active compounds. Toward this fact, the enantioselective synthesis of alpha-hydroxy carboethoxy cyclohexenone scaffold has been accomplished by following the routes which were manganese(III) acetate-mediated chemical oxidation followed by enzyme-mediated hydrolysis and additionally microbial direct biooxidation by whole cells of fungi expressly A. oryzae and A. flavus. A very satisfying results have been obtained by both of the methods.