Novel Transformations and Applications of the Biomass Pyrolysis Product Levoglucosenone

Abstract

<p>The cellulose-derived species, levoglucosenone (LGO), has only recently become available in large quantities although it was first identified in 1973. The increased availability of this chiral, biorenewable starting material means that its potential uses in synthesis can be examined. Therefore, this thesis is aimed at further expanding the repertoire of reactions known for LGO and to synthesise several targets via these reactions.</p> <p>Chapter 2 details the microwave-optimised Suzuki-Miyaura arylation of 3-iodolevoglucosenone. Microwave irradiation, compared to conventional heating, provided greatly improved reaction times while giving similar yields. This development allowed for rapid access to a range of 3-aryl derivatives of LGO.</p> <p>The 3-aryl derivatives were used to explore Johnson-Corey-Chaykovsky cyclopropanation in Chapter 3. The use of an unstabilised sulfoxonium ylide and 1,1,3,3-tetramethylguanadine (TMG) in dimethyl sulfoxide afforded a range of 1,2-trisubstituted cyclopropane derivatives in excellent yield. Furthermore, a range of 1,2,3-tetrasubstituted cyclopropane derivatives were produced in high yield using stabilised sulfonium ylides and TMG in tetrahydrofuran. Cyclopropanation reactions proceeded with high diastereoselectivity due to the preferential approach of the ylide to the exo-face of the bicyclic ring system</p> <p>In Chapter 4 two known central nervous system bioactive compounds were synthesised from two different cyclopropane derivatives, prepared in Chapter 3. The enantioselective synthetic pathways involved Baeyer-Villiger oxidation, butyrolactone opening and oxidative cleavage to dehomologate the chain giving an aldehyde that was then reductively aminated. The methods developed to access these bioactive compounds have a comparable number of steps to the previously published procedures.</p> <p>The incorporation of a benzyl group to the α-carbon of dihydrolevoglucosenone was explored in Chapter 5. The most efficient method of producing an α-benzyl derivative of dihydrolevoglucosenone was determined to be via an aldol condensation. The scope of the reaction was explored using several benzaldehydes to give a range of benzylidenes. Subsequently, the unsubstituted benzylidene was then reduced to afford an α-benzyl derivative and further transformed into enantiomerically pure (<i>3R,5S</i>)-3-benzyl-5-(hydroxymethyl)dihydrofuran-2(<i>3H</i>)-one, which is an intermediate in the synthesis of the commercial protease inhibitor, indinavir.</p> <p>Chapter 6 explored the incorporation of nitrogen groups onto the levoglucosenone scaffold through aza-Michael addition and aziridination reactions. Aza-Michael addition to levoglucosenone was possible with aliphatic amines under aqueous conditions, however, to avoid product decomposition the β-aminoketones were reduced to alcohols <i>in situ</i>. The β-amino alcohol derivatives were isolated in moderate to excellent yield with varying diastereomer ratios, which were dependent on the amine group. Aziridination of 3-iodolevoglucosenone was achieved with several primary amines to produce aziridine derivatives in moderate to excellent yield. These aziridine derivatives were further transformed via ring-opening aza-Wharton reactions to afford allylic amines in moderate to high yields. The nitrogen containing scaffolds reported in this chapter could be utilised in the development of novel, bioactive aminoglycosides.</p> <p>Lastly, Chapter 7 details the unprecedented direct Weitz-Scheffer epoxidation of LGO and 3-aryl derivatives. Using anhydrous <i>tert</i>-butyl hydroperoxide and the non-nucleophilic base 1,8- diazabicyclo[5.4.0]undec-7-ene, the epoxide derivatives were afforded with short reactions times and in good to excellent yield. The key to this chemistry was the finding that water had to be excluded due to the formation of hemiacetals. The epoxides were subsequently subjected to Wharton conditions to produce allylic alcohols and then oxidised to afford the constitutional isomers of LGO and the 3-aryl derivatives in good yields. These pseudo-isomers were therefore accessible from the initial enones in three simple steps and allow for further investigation of their reactivity and possible future application in targeted synthesis.</p>