Protected DHA units, known as dioxanones, are interesting compound which can be used as the building blocks for synthesis of polyoxygenated natural products. The direct aldol reaction is employed for converting of those inexpensive starting materials into enantioenriched products of complexed structures. The stereocontrol in the first aldol reaction is achieved by using organocatalysis. Second aldol reaction is conducted by lithium enolate chemistry leading to anticisanti aldols as a major isomer. On the other hand boron chemistry provides antitransanti products. This strategy is used for synthesis of higher sugars.

Protected DHA units, known as dioxanones, are interesting compound which can be used as the building blocks for synthesis of polyoxygenated natural products. The direct aldol reaction is employed for converting of those inexpensive starting materials into enantioenriched products of complexed structures. The stereocontrol in the first aldol reaction is achieved by using organocatalysis. Second aldol reaction is conducted by lithium enolate chemistry leading to anticisanti aldols as a major isomer. On the other hand boron chemistry provides antitransanti products. This strategy is used for synthesis of higher sugars.

No description available.

No description available.

This thesis focuses on the use of unsaturated aldols as useful substrates in natural product synthesis. Two methodologies have been investigated for the asymmetric synthesis of highly substituted lactones containing multiple contiguous stereocentres from unsaturated aldol precursors. These lactones have potential application as building blocks for natural product synthesis. Firstly, synthetic applications of the retro aldol reaction are reviewed. The second chapter describes a novel methodology for the asymmetric synthesis of highly substituted δ-lactones from syn-aldol cyclopropanes iii. Mercury mediated cyclopropane ringopening of the methyl ester cyclopropanes iv followed by concomitant cyclisation produced organomercurial δ-lactones v, which subsequently undergo reductive demercuration in basic sodium borohydride to afford the highly substituted δ-lactones vi in good yield and excellent diastereoselectivity. The scope of this method was investigated with variation of the R1 and R2 groups. The synthetic utility of this process was also demonstrated with the synthesis of a series of (+)-Prelactone natural products. The third chapter decribes a method of preparing hydroxy-γ-butyrolactones (viii-x) containing multiple contiguous stereocentres in high yield with good diastereoselectivity. Upjohn dihydroxylation conditions using catalytic osmium tetroxide were employed to β-alkenyl-β- hydroxy-N-acyloxazolidin-2-ones vii with different alkene substitution patterns. This resulted in the formation of triols that underwent spontaneous intramolecular 5-exo-trig cyclisation reactions to afford hydroxy-γ-butyrolactones viii, ix or x depending on the substitution pattern of the alkene precursor.

The sequential aldol reactions of thiopyran derivatives 112 and 119 to rapidly generate hexapropionate building blocks in two carbon-carbon forming steps has been well studied within the Ward group. An extension of this strategy to generate non-racemic tetra- and hexapropionate fragments involved the use of non-racemic 119 which was obtained via resolution of the acid derivate 131. <p> Part of the present work concerns the preparation of non-racemic 119 via enantioselective protonation of various thiopyran based ester derivatives. The trend observed in the ee obtained for the various ester derivatives is consistent with what has been previously observed by other groups. <p> Section 2.3 discusses the use of β-ketocarbonyl analogues of thiopyranone in vinylogous aldol reactions. A β-ketocarbonyl analogue was prepared and shown to undergo stereoselective aldol reactions under previously established condtions. The stereoselectivities of the reactions were in all cases consistent with what has been previously observed for the aldol reactions of 112 and 119 within the group. <p> Section 2.4 discusses the preparation of a meso dialdehyde derivative of thiopyranone (196) and its use in a simultaneouse two directional aldol reaction to generate a hexapropionate building block with six stereocenters in a one pot reaction. The meso adduct 202as generated was successfully desymmetrized via enantioselective enolization to afford an enantioenriched adduct with seven stereogenic centers. <p> The meso dialdehyde 196 was also desymmetrized via an enantiotopic group selective aldol reaction promoted with (S)-proline. This reaction proceeds via a dynamic kinetic and thermodynamic resolution to afford a single stereoisomer. The enantioenriched aldol adduct was converted to a tetrapropionate unit and also demonstrated after derivatization to undergo a second aldol reaction affording a non-racemic hexapropionate synthon. This chemistry is discussed in section 2.5. <p> Section 2.6 discuses the assignment of the relative and absolute configurations of the various aldol adducts via NMR and X-ray. <p> To demonstrate the synthetic usefulness of this research, the hexapropionate synthon 202as was used as a template towards the confirmation or reassignment of the core spiroketal structure reported for enteridic acid.

The sequential aldol reactions of thiopyran derivatives 112 and 119 to rapidly generate hexapropionate building blocks in two carbon-carbon forming steps has been well studied within the Ward group. An extension of this strategy to generate non-racemic tetra- and hexapropionate fragments involved the use of non-racemic 119 which was obtained via resolution of the acid derivate 131. <p> Part of the present work concerns the preparation of non-racemic 119 via enantioselective protonation of various thiopyran based ester derivatives. The trend observed in the ee obtained for the various ester derivatives is consistent with what has been previously observed by other groups. <p> Section 2.3 discusses the use of β-ketocarbonyl analogues of thiopyranone in vinylogous aldol reactions. A β-ketocarbonyl analogue was prepared and shown to undergo stereoselective aldol reactions under previously established condtions. The stereoselectivities of the reactions were in all cases consistent with what has been previously observed for the aldol reactions of 112 and 119 within the group. <p> Section 2.4 discusses the preparation of a meso dialdehyde derivative of thiopyranone (196) and its use in a simultaneouse two directional aldol reaction to generate a hexapropionate building block with six stereocenters in a one pot reaction. The meso adduct 202as generated was successfully desymmetrized via enantioselective enolization to afford an enantioenriched adduct with seven stereogenic centers. <p> The meso dialdehyde 196 was also desymmetrized via an enantiotopic group selective aldol reaction promoted with (S)-proline. This reaction proceeds via a dynamic kinetic and thermodynamic resolution to afford a single stereoisomer. The enantioenriched aldol adduct was converted to a tetrapropionate unit and also demonstrated after derivatization to undergo a second aldol reaction affording a non-racemic hexapropionate synthon. This chemistry is discussed in section 2.5. <p> Section 2.6 discuses the assignment of the relative and absolute configurations of the various aldol adducts via NMR and X-ray. <p> To demonstrate the synthetic usefulness of this research, the hexapropionate synthon 202as was used as a template towards the confirmation or reassignment of the core spiroketal structure reported for enteridic acid.

This thesis describes the syntheses of some polyfunctionalised cyclopentanes via intramolecular aldol condensations of sugar δ-lactone precursors. The known azido carbpcycle (1S,2R,3S,4R,5R)-methyl [5-azido-1,2,3,4- tetrahydrpxy-2,3-O-isopropylidene-cyclopentane] carboxylate was prepared from 2- deoxy-2-iodo-3,4:6,7-di-O-isopropylidene-D-glycero-D-talo-heptono-1,5-lactone in five steps. The key reaction was a base-induced intramolecular aldol cyclisation of a 5- iodo-formyl-2,6-lactone. Borohydride reduction of the methyl ester gave an azido triol. Deprotection followed by reduction of the azide functionality produced an amino pentol. The analogous tetrahydroxy β-amino acid was synthesised from the azido carbocycle in three steps. The inhibitory activity of the amino pentol against human liver glycosidases is reported. Two azido bicyclic lactones, (1R,4R,5R,6R,7R)-4-azido-5,6,7-trihydroxy-5,6-0- isopropylidene-2-oxa-bicyclo[2.2.1]heptan-3-one and (1S,4S,5R,6R,7R)-4-azido- 5,6,7-trmydroxy-5,6-O-isopropydilene-2-oxa-bicyclo[2.2.1]heptan-3-one, were prepared from 3,4:6,7-di-O<./em>-isopropylidene-D-glycero-D-talo-heptono-1,5-lactone in five steps. The (1R,4R,5R,6R,7<em.R)-compound was further elaborated to give an amino pentol via a series of borohydride reduction / deprotection / catalytic hydrogenation. A novel carbocyclic spirohydantoin was synthesised by two alternative routes. The second route also provided access to an N'-phenyl spirohydantoin. The inhibitory activities of the amino pentol and the spirohydantoin against human liver glycosidases are reported. The azido bicyclic lactone triol (1R,4S,5R,6R,7R)-4-azido-5,6,7-trihydroxy-2-oxabicyclo[ 2.2.1]heptan-3-one underwent reduction of the azide functionality with concomitant epimerisation to give the (5S)-epimeric amine. The structure of this material was confirmed by X-ray diffraction analysis of a crystalline derivative. Treatment of the azido triol with base under non-aqueous conditions resulted in a retroaldol reaction to give the (5S)-epimeric azide, the relative configuration of which was determined by single crystal X-ray analysis. A third ketal protected azido bicyclic lactone was prepared via a base-induced retro-aldol epimerisation. Five tetrahydroxycyclopentane α-amino acids, including a pair of enantiomers, were synthesised from the azido bicyclic lactones. The structures of two of the α-amino acids were established by X-ray crystallographic analysis, whilst the enantiomeric compounds were identified using circular dichroism spectrometry. The diketal protected (2R,3R,4R,5R)-tetrahydroxy-cyclopentane α-amino acid was incorporated into six oligopeptides. Peptide coupling at the C-terminus of the carbocyclic amino acid was carried out using two amino acid tert-butyl esters. Chain extension at the N-terminus was achieved by reaction with N-benzyloxycarbonyl protected amino acids in the presence of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride as the carbodiimide reagent. Complete deprotection of a tetrapeptide is described.

No description available.

In the Ward Group, stereoselective aldol reactions of thiopyran derived templates play an important role in polypropionate natural product syntheses. Central to this approach is the diastereo- and enantioselective synthesis of all possible aldol adducts 3 arising from tetrahydro-4H-thiopyran-4-one (1) and 1,4-dioxa-8-thiaspiro[4.5] decane-6- carboxaldehyde (2). There are four possible diastereomers of 3 indicated by the relative configurations at positions 3 and 1’ (syn or anti) and positions 1’ and 6’ (syn or anti). Up to date, the asymmetric aldol reaction of 1 with 2 catalyzed by L-proline or its tetrazole analogue 12 provides efficient access to 3,1’-anti-1’,6’-syn-3 (3-AS) without need for chromatography (>40 g scale; 75% yield, >98% ee) and 3,1’-syn-1’,6’-syn-3(3-SS) (via isomerization of 3-AS; >75% yield, 2 cycles); however, the preparation of enantiopure 3,1’-anti-1’,6’-anti-3 (3-AA) and 3,1’-anti-1’,6’-syn-3 (3-SA) still requires the use of enantiopure aldehyde 2 in a diastereoselective synthesis. Without a simple and scalable route, access to enantioenriched iterative aldol adducts and polypropionate natural products that are based on 3-AA and 3-SA skeletons are hindered. It was observed that conducting the asymmetric aldol synthesis of 3-AS on large scale gave enantioenriched 3-AA as a very minor product. This observation triggered the hypothesis of using L-proline to resolve racemic 3-AA via a retro-aldol reaction.In this thesis, the development, optimization, and application of an unprecedented L-proline catalyzed enantioselective retro-aldol reaction is described. Interesting mechanistic insights were uncovered. An unexpected isomerization process between 3-AA and 3-SA occurs in parallel with the retro-aldol process. The method was demonstrated to be a robust, flexible, and readily scalable process to access highly enantioenriched 3-AA (ee > 95%) and 3-SA (ee > 95%). To the best of our knowledge, this reaction represents the only reported enantioselective retro-aldol reaction catalyzed by L-proline.