Thiopyran route to polypropionates : increasing stereochemical diversity of aldol adducts
Linear carbon-carbon chains with alternating hydroxyl and methyl substituents are a common motif in various natural products. Many of these so-called polypropionates show biological activity and are useful in the fields of medicine and agriculture. The stereoselective synthesis of polypropionates has been extensively investigated and numerous strategies and tactics have been developed. The sequential aldol reactions of thiopyran derivatives 122 and 125 followed by desulfurization of aldol adducts is a strategy to rapidly construct hexapropionate synthons (e.g. 165). The present work concerns the control of the stereoselectivity in the two key aldol coupling steps inherent in this strategy. In Section 2.2, the influence of reaction conditions and the relative configuration of the â-alkoxy group of aldehydes cis-125b and trans-125c on the diastereoselectivity of the 1st aldol coupling are discussed. The results were rationalized according to Evan's merged 1,2- and 1,3-stereoinduction model (nonchelation), with the exception of the MgBr2•OEt2 promoted reactions of 137b (M = TMS) with 125a, 125b and 125c, which were accommodated by assuming chelation control. Under appropriate conditions, three (126a-128a) of the four possible diastereomers could be obtained stereoselectively. The fourth diastereomer (129a) was readily available by isomerization (vide infra). In Section 2.3, the diastereoselectivities of the aldol reactions of (±)-125a with (±)-126a and (±)-127a (previous work) and reactions of (±)-125a with (±)-128a and (±)-129a (this work) are presented. These reactions occurred with high mutual kinetic enantioselection (MKE) and were highly diastereoselective for the formation of one out of eight possible diastereomers. The diastereoselectivity of aldol reactions of (±)-125a with related â-alkoxy ketones (±)-166 and (±)-168 (previous work) and reactions with enantioselection (MKE) and were highly diastereoselective for the formation of one out of eight possible diastereomers. The diastereoselectivity of aldol reactions of (±)-125a with related â-alkoxy ketones (±)-166 and (±)-168 (previous work) and reactions with (±)-172 and (±)-174 (this work) were also investigated. Contrary to the aldol reactions of â-hydroxy ketones (126a-129a), reactions of â-alkoxy ketones (166, 168, 172, 174) proceeded without significant MKE. These reactions were also highly diastereoselective giving two products, one each from the like and unlike reactions. In Section 2.4, the use of imidazole as an effective catalyst for syn/anti isomerization of aldols via keto-enol tautomerism is described. A large variety of aldol (e.g. 126) and bisaldol (e.g. 165) adducts were shown to undergo efficient isomerization with minimal retroaldol and elimination reactions. The rate constants for this process were determined for several substrates. It was found that thiopyranone derived aldols isomerize much faster than related cyclohexanone aldols and the â-hydroxy ketones (e.g. 128a) isomerize faster than â-alkoxy derivatives (e.g. 172). In section 2.5, the relative configuration of aldol adducts was rigorously determined using chemical correlations and NMR methods.
Doctor of Philosophy (Ph.D.)