Thiopyran Route to Polypropionates:  Aldol Diastereoselectivity of Linear and Two-Directional Iterative Homologations

Abstract

[formula: see text] Aldol reaction of tetrahydro-4H-thiopyran-4-one with racemic 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde is easily controlled to give the 2,3-anti-3,4-syn or the 2,3-syn-3,4-syn adduct. Aldol homologations of these beta-hydroxy ketones with the same aldehyde occur with considerable mutual kinetic enantioselection (MKE) and, in each case, selectively give one of the eight possible diastereomers. Similar reactions of related beta-methoxy ketones are also very diastereoselective but proceed without significant MKE, resulting in two diastereomers. The adducts can be used for polypropionate synthesis.

Syn−Anti Isomerization of Aldols by Enolization

“…We have been exploring the stereoselectivities of sequential aldol reactions of 8 and 10 as the foundation of a thiopyran-based synthetic route to polypropionates. 18,19 The propensity of imidazole to isomerize tetrahydrothiopyranone-derived aldols was first observed during a failed attempt to protect the hydroxyl group in 7a 18 by reaction 20 with TBDMSCl in the presence of an excess of imidazole in CH 2 Cl 2 ; after 5 days, approximately 30% of 7s 18 was detected and isolated from the reaction mixture. That imidazole was responsible for the isomerization was readily demonstrated by monitoring a CDCl 3 solution of 7a containing 10 equiv of imidazole (ca.…”

“…To further explore the generality of process and the effects of structure on reactivity, isomerizations of the R-methyl aldols 19 and 20 33 (Scheme 3) 34 and the bisaldol derivatives 21-24 19 (Schemes 4 and 5) were investigated. In these cases, isomerization can occur through regioisomeric enols producing a four-component equilibration.…”

The thiopyran route to polypropionates

“…Aldol (À)-55as is a versatile tetrapropionate synthon that can be utilized as a precursor for both anti-syn and syn-anti stereotriads because of its differentiated 1,5-dione functionality (Scheme 16). 61 Moreover, (À)-55as is readily isomerized via keto-enol tautomerism to a 2.5 : 1 equilibrium mixture of (+)-55ss and (À)-55as, respectively, by treatment with imidazole in CH 2 Cl 2 40 or more conveniently, by exposure to Et 3 N and SiO 2 . 62 This process is very efficient and allows the synthesis of (+)-55ss on preparative scale in >50% yield in three operations from 4 and (AE)-54.…”

“…according to the procedure 70 of Luke and Morris and led to the isolation of three aldol adducts: meso 99a (60%), (AE)-99b (6%), and (AE)-99e (4%). 61 Further optimization of the conditions using Ti(O i Pr)Cl 3 in place of TiCl 4 and adding the i Pr 2 EtN in two portions produced 99a in excellent yield with remarkable stereoselectivity (dr > 30). 71 This synthesis of 99a constitutes a rare (perhaps unique) example of the formation of a meso compound by stereoselective coupling of racemic fragments.…”

Syn−Anti Isomerization of Aldols by Enolization

“…We also examined the imidazole-catalyzed isomerization of the bisaldols 11 (Table ). Reactions of 11aa or 11sa in all cases led to a mixture of the same three aldols, clearly indicating isomerization by an enolization mechanism…”