THE TOTAL SYNTHESIS OF DOLABRIFEROL C VIA ONE-POT ENANTIOSELECTIVE BISALDOL REACTIONS

Dolabriferol C is a member of a small family of marine natural products known as non-contiguous polypropionates that are esters of a polypropionate carboxylic acid with a polypropionate alcohol. The origin of these so-called ‘natural products’ is uncertain, but they are often hypothesized to arise from a retro-Claisen fragmentation of a hemiacetal formed from a 5-hydroxy-1,3-dione embedded in a contiguous polypropionate chain. To test that conjecture, these putative precursors have been targeted for total synthesis to allow exploration of their properties, especially the tendency to rearrange into the non-contiguous ‘natural products’. In previous work, the Ward group produced experimental evidence for the proposed origin of non-contiguous polypropionates baconipyrone A, baconipyrone C, and dolabriferol by total synthesis from their putative contiguous precursors via a retro-Claisen approach. Towards the synthesis of the putative contiguous precursor of dolabriferol C, a new strategy was contemplated and examined the potential of bisenolates of meso 1,5-diketones, previously unknown entities. The research presented herein describes the development and application of one-pot sequential enantiotopic group selective (SEGS) aldol reactions as a powerful strategy for highly convergent polypropionate synthesis. Both (E,E)- and (Z,Z)- meso bisenol borinates were prepared stereoselectively from meso 1,5-diketones, and were successfully used in enantioselective desymmetrization and SEGS bisaldol reactions to synthesize several meso, racemic, and enantiopure polypropionate motifs with high diastereoselectivities. The putative contiguous precursor was prepared via a highly stereoselective bisaldol reaction of a meso 1,5-diketone with two different chiral aldehydes that generates the full carbon skeleton of the precursor and sets the absolute configuration of eight stereocenters in a one-pot process. Brief exposure of the putative precursor to neutral alumina cleanly produced dolabriferol C via a remarkably chemoselective retro-Claisen reaction thereby establishing this natural product as a plausible isolation artifact. This is the first total synthesis of dolabriferol C (and the putative contiguous precursor) and was achieved in 7 steps with 13.6% overall yield from the known enantiopure aldehyde. Using this strategy, an improved synthesis of dolabriferol was also achieved in 5 steps with 34% overall yield from the known enantiopure aldehyde

The thiopyran route to polypropionates : sequential enantiotopic group selective enolization of meso 1,9-diketones

Meso 1,9-diketones (six to seven stereocenters)are readily obtained by stepwise or simultaneous two-directional aldol reactions of tetrahydro-4H-thiopyran-4-one with a thiopyran-derived aldehyde. Enantioselective enolizations of these diketones with the lithium amide from (R,R)-bis(1-phenylethyl)amine occur with simultaneous kinetic resolution to give the mono-TMS enol ethers in >90% yields based on recovered starting material (BORSM) and >90% ee. The developed methodology was applied in synthetic studies towards the asymmetric synthesis of denticulatin A

Osmium Catalyzed Dihydroxylation And Oxidative Cleavage Of Vinyl Sulfone And Elucidation Of The Vinylsulfone Polypropionate Methodology For The Synthesis Of The C32 Des-Methyl C28-C34 Actin Binding Tail Of Aplyronine A

A general methodology for the generation of dipropionate functionalities using cyclic 7-membered vinylsulfones has been devised for the purpose of synthesizing polyketide natural products such as aplyronine A. Final oxidative cleavage via ozonolysis has been shown to be difficult providing variable yields. Furthermore, elegant synthesis of the C28-C34 segment of the aplyronine A actin binding tail has proved elusive. Utilization of OsO4 and catalytic citric acid has led to a methodology whereby harsh ozonolysis procedures can be mostly avoided. A reengineering of the vinylsulfone polypropionate methodology in conjunction with osmylation has been found to provide the actin binding tail under mild high yielding conditions. These discoveries will be key in developing a methodology for providing highly complex large scale substrates for the synthesis of asymmetric natural products

Catalytic Asymmetric Aldol Equivalents for an Enantioselective Total Synthesis of Apoptolidin C

Apoptolidin C is a biologically active polypropionate macrolide isolated from the soil bacteria Nocardiopsis sp. The work presented herein highlights a novel approach to synthesizing the core of the natural product, apoptolidinone C, as well as a de-novo synthesis of the C9 sacharide. Our synthesis utilizes a catalytic asymmetric approach to the construction of the complex polypropionate arrays contained in apoptolidin through the use of our acyl halide-aldehyde cyclocondensation (AAC) reaction. Employing the AAC technology using cinchona alkaloid derived catalysts, as well as the complementary chiral aluminum catalysts, we have successfully demonstrated a catalytic and asymmetric synthesis of the aglycone core of apoptolidin C. In addition, we have demonstrated the asymmetric synthesis of the C9 saccharide from achiral starting materials

Characterization of Onchidiid Slug (Onchidium typhae) West Kalimantan Waters as Antibacterials and Antifungal

Onchidiid slug (Onchidium typhae) is a nudibranch that coastal communities in West Kalimantan have widely used as wounds. The study aims to characterize the West Kalimantan water O. typhae as antibacterial and antifungal. The study of O. typhae was carried out in several stages: preparation and optimization, extraction by Quinn method, characterization and identification of bioactive compounds, and antibacterial and antifungal assay using the microdilution method. The result of the proximate test showed that O. typhae powder contains high protein, namely 67.68%. Phytochemical screening results from methanol, ethyl acetate, and chloroform extracts contain alkaloids and amino acids. Methanol, chloroform, and ethyl acetate extract 1% of O. typhae showed inhibitory activity against Staphylococcus aureus, Escherichia coli, and Candida albicans. The most significant inhibition value was indicated by chloroform extract 1%, where the inhibition value against S. aureus, E. coli, and C. albicans was 82±0.01%; 85.8±0.01%; 85±0.01%, respectively. From these results, O. typhae powder can be developed as a wound medicine through its antibacterial and antifungal activity

Use of sultines in the asymmetric synthesis of polypropionate antibiotics

At low temperature and in the presence of an acid catalyst, SO2 adds to 1,3-dienes equilibrating with the corresponding 3,6-dihydro-1,2-oxathiin-2-oxides (sultines). These compounds are unstable above -60 °C and equilibrate with the more stable 2,5-dihydrothiophene 1,1-dioxides (sulfolenes). The hetero-Diels-Alder additions of SO2 are suprafacial and follow the Alder endo rule. The sultines derived from 1-oxy-substituted and 1,3-dioxy-disubstituted 1,3-dienes cannot be observed at -100 °C but are believed to be formed faster than the corresponding sulfolenes. In the presence of acid catalysts, the 6-oxy-substituted sultines equilibrate with zwitterionic species that react with electron-rich alkenes such as enoxysilanes and allylsilanes, generating β,γ-unsaturated silyl sulfinates that can be desilylated and desulfinylated to generate polypropionate fragments containing up to three contiguous stereogenic centers and an (E)-alkene unit. Alternatively, the silyl sulfinates can be reacted with electrophiles to generate polyfunctional sulfones (one-pot, four-component synthesis of sulfones), or oxidized into sulfonyl chlorides and reacted with amines, then realizing a one-pot, four-component synthesis of polyfunctional sulfonamides. Using enantiomerically enriched dienes such as 1-[(R)- or 1-(S)-phenylethyloxy]-2-methyl-(E,E)-penta-1,3-dien-3-yl isobutyrate, derived from inexpensive (R)- or (S)-1-phenylethanol, enantiomerically enriched stereotriads are obtained in one-pot operations. The latter are ready for further chain elongation. This has permitted the development of expeditious total asymmetric syntheses of important natural products of biological interest such as the baconipyrones, rifamycin S, and apoptolidin

The Total Synthesis of Dolabriferol: A retro-Claisen Approach from its Putative Precursor

Dolabriferol is a polypropionate natural product first isolated by Gavagnin and coworkers from the skin of the anaspidean mollusk, Dolabrifera dolabrifera. An unusual structural feature of dolabriferol is its noncontiguous carbon backbone that is proposed to arise via a retro-Claisen rearrangement of a cyclic hemiacetal precursor, perhaps as an artifact of isolation. Computational evaluations of the various cyclization/rearrangement manifolds available to the acyclic precursor have suggested that the pathway to dolabriferol from its linear precursor is plausible. The research presented herein describes the total synthesis of the putative precursor, evaluation of its properties, and a study of its retro-Claisen rearrangement. This study ultimately gave dolabriferol which suggests this compound may be formed during isolation; thus, the linear precursor (along with its tautomeric forms) is a plausible natural product. This is the first total synthesis of dolabriferol via its putative precursor

Thiopyran route to polypropionates : proline catalyzed aldol reactions of tetrahydro-4H-thiopyran-4-one

The thiopyran route to polypropionates is an attractive strategy that involves a stepwise iterative aldol homologation of tetrahydro-4H-thiopyran-4-one (I) with thiopyran aldehyde (II) followed by desulfurization to rapidly assemble stereochemically complex polypropionate synthons. In chapter 1, the thesis is summarized in the context of relevant background research including; a) the basic principle of the thiopyran route; b) dynamic kinetic resolution of -substituted aldehydes; c) previous syntheses of serricornin; iv) previous syntheses of membrenones.In chapter 2, proline-catalyzed enantioselective direct intermolecular aldol reactions of tetrahydro-4H-thiopyran-4-one with various achiral aldehydes were studied. The results provided insights on the behaviour and stereoselectivity profile of thiopyranone (a crucial starting block in the thiopyran design) in the proline-catalyzed aldol reaction.In chapter 3, inspired by the results of the aldol reaction of ketone (I) with achiral aldehydes, we next investigated the proline-catalyzed asymmetric aldol reactions of (I) with racemic thiopyran aldehyde (II) as a strategy to rapidly prepare enantiomerically pure tetrapropionate synthons without any requirement of enantioenriched aldehyde. The reaction occurred with high enantiotopic group selectivity and dynamic kinetic resolution.In chapter 4, a detailed study to ascertain the scope and limitations of the design strategy described in chapter 3 was extended towards other catalysts, aldehydes and ketones. Finally, applications of the above mentioned strategy towards the synthesis of serricornin and membrenones A and B are elaborated in chapters 5 and 6 respectively