STEREOCHEMICAL DIVERSITY IN THE SUBSTRATE-CONTROLLED STEREOSELECTIVE ALDOL COUPLINGS OF CHIRAL REACTANTS
Jana, Sushital 1988-
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Undoubtedly, stereoselective aldol coupling is one of the most powerful tools available for synthetic chemists to effectively couple two non-racemic fragments in the late-stage of a total synthesis. Many successful applications of this strategy in polypropionate natural product syntheses have been reported. Notwithstanding these successful attempts, several examples have also been reported where the aldol coupling afforded undesired stereoisomers or resulted in surprisingly low diastereoselectivities. Consequently, either the route was no longer pursued (and a different disconnection approach was used) or the efficiency of the synthesis was compromised due to the low diastereoselectivities of the aldol couplings. Because the structure of the fragments to be coupled are dictated by the target molecule, significant changes of these structures would greatly influence the efficiency of the synthesis. A more cost-effective and practical solution to the aforementioned problems would require only simple modifications of the substrates (e.g., variation of protecting groups) or the reaction conditions (e.g., change in enolate type or geometry, temperatures) to alter the outcome of the reaction. Having a general approach toward polypropionates would overcome the aforementioned issues where most (if not all) of the possible diastereomers of an aldol coupling can be selectively accessed. Toward that end, the Ward group has designed aldol couplings that proceed with kinetic resolution (thiopyran route to polypropionates, TR2P) and accessed three (aas, ass, and sas) of the eight possible diastereomers (all Felkin) in their non-racemic form. This work also showed that with proper knowledge of each of the three stereocontrol elements (i.e., diastereoface selectivities of aldol additions to the ketone enol(ate) and aldehyde and the relative topicity of coupling), rational design of aldol couplings proceeding with kinetic resolution is possible. The objective of my research was to access the remaining five of the eight possible diastereomers by extending the TR2P to acyclic ketones and thereby, increase the stereochemical diversity in the aldol couplings of chiral fragments. After identifying suitable substrates and reactions conditions (from the model reactions where one of the coupling fragments was achiral), aldol couplings of chiral aldehydes with enolates of chiral ketones were performed under those reaction conditions in which the diastereoface selectivities of the aldol additions were high with respect to each of the coupling fragments. Aldol couplings of (E)-enol borinates proceeded with excellent mutual kinetic enantioselections (MKEs) and provided sas (racemic) as the predominant product. In contrast, the aldol couplings of Ti(IV) (Z)-enolates proceeded with good to moderate MKEs and provided sss (racemic) as the major product. Aldol couplings with nonracemic ketones (i.e., kinetic resolution) provided enantioenriched sas and sss aldol adducts. This developed methodology (i.e., acyclic route to polypropionates, AR2P) provided access to two aldol diastereomers sas and sss (both Felkin). All attempts to obtain the remaining four (non-Felkin) diastereomers under kinetically controlled reaction conditions failed. Serendipitously, isomerization of Mg(II) aldolates (prepared by reaction of aldol adducts with i-PrMgBr) under thermodynamic control provided access to two (ssa and asa) of the remaining four non-Felkin diastereomers in non-racemic form. Under optimized conditions, good yields and excellent product diastereoselectivities favoring the non-Felkin aldols were obtained with several substrates. The product distribution under thermodynamic control was found to be strongly dependent on the chelating ability of the aldehyde component of the aldol adduct. In favorable cases, the combination of kinetically controlled aldol couplings (TR2P and AR2P) with the above isomerization process provided selective access to six of the eight possible diastereomers in their non-racemic form. These aldol adducts have numerous applications in polypropionate natural product syntheses. The increased stereochemical diversity should provide more flexibility in the retrosynthetic design of polypropionate natural products.
DegreeDoctor of Philosophy (Ph.D.)
SupervisorWard, Dale E.
CommitteeMueller, Jens; Pedras, Soledade; Low, Nicholas; Grosvenor, Andrew
Copyright DateMarch 2019
mutual kinetic enantioselection