Influence of the β-Alkoxy Group on the Diastereoselectivity of Aldol Reactions of Tetrahydro-4H-thiopyran-4-one with 4-Alkoxytetrahydro-2H-thiopyran-3-carboxaldehydes

Abstract

The diastereoselectivity of the aldol reaction of tetrahydro-4H-thiopyran-4-one (3) with 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde (9a) under a variety of conditions is examined. Under optimized conditions, three of the four possible diastereomers from this aldol reaction can be obtained selectively (3-16:1). Reactions of 9a with the Li, B, Mg(II), and Ti(IV) enolates of 3 and with the corresponding trimethylsilyl enol ether 4b in the presence of BF(3) x OEt(2), SnCl(4), or TiCl(4) as promoters gave the Felkin adducts exclusively (>95%) as mixtures of syn (11a) and anti (12a) diastereomers. Use of the "amine-free" Li enolate of 3 gave 12a with a much higher diastereoselectivity (9:1) and yield (70%) than that obtained using the lithium diisopropylamide-generated Li enolate of 3 (2-3:1; 15-40%). The TiCl(4)-promoted reaction of 4b with 9a gave 11a with excellent selectivity (16:1). In contrast, the MgBr(2) x OEt(2)-promoted reaction of 4b with 9a gave the anti-Felkin adducts exclusively as a 3:1 mixture of syn (13a)/anti (14a) diastereomers. Similar aldol reactions of 3 with the cis and trans isomers of 4-(methoxy)methoxytetrahydro-2H-thiopyran-3-carboxaldehyde (9b and 9c) were examined to probe the influence of the ketal protecting group in 9a on the observed aldol diastereoselectivity. The results are rationalized by applying Evans' stereochemical model for merged 1,2- and 1,3-asymmetric induction (non-chelation), with the exception of the MgBr(2) x OEt(2)-promoted reactions of 4b with 9a, 9b, and 9c, which are accommodated by assuming chelation control. Comparison of the reactions of 9a, 9b, and 9c suggests that the ketal group in 9a uniquely allows high levels of either Felkin or anti-Felkin selectivity to be achieved.

Enantioselective Direct Aldol Reactions of Achiral Ketones with Racemic Enolizable α-Substituted Aldehydes: Scope and Limitations

“…As shown previously, 17 the dioxolan group in 2a (and 2b) imparts a very strong Felkin bias for addition to the carbonyl, and this feature is essential for effective kinetic resolution. 3c To test this aspect, we attempted the reaction of 1 with (±)-14 in hopes of effecting a type III dynamic kinetic asymmetric transformation (DYKAT, 18 Table 2).…”

Polypropionate Synthesis via Substrate‐Controlled Stereoselective Aldol Couplings of Chiral Fragments

“…Similar reactions of the analogous anti-12 aldehydes were much less selective (13as/13sa adducts, 0.3-2 : 1). Increased diastereoface selectivity favoring the formation of 1,2-anti products was also observed from a conformationally rigid 2,3-syn aldehyde compared to its 2,3-anti diastereomer (i.e., with C2-C3 part of a six-membered ring) under chelating conditions [56]. It is noteworthy that Guindon et al [58] were able to achieve excellent diastereoselectivity in favor of the 1,2-anti products from both aldehyde diastereomers syn-12 (13aa; dr > 20) and anti-12 (13as; dr > 20) in a related series (R = CH 2 OBn; Pg = Bn; Nu = Me(Br)C=C(OMe)OTMS) by reactions via cationic Ti(IV) chelates (i.e., LA = Cl 2 (Oi-Pr)Ti (+) ) formed with excess Ti(Oi-Pr)Cl 3 .…”

“…That is, the less selective (dr < 4) unless the nucleophile was sterically very bulky; with an unhindered nucleophile, the 13aa products were formed with excellent selectivity in favorable cases (e.g., with a PMB protecting group in a nonpolar solvent) [55]. Increased diastereoface selectivity favoring the formation of 1,2-syn products was also observed from a conformationally rigid 2,3-anti aldehyde compared to its 2,3-syn diastereomer (i.e., with C2-C3 part of a six-membered ring) [56].…”

Total Synthesis of Polypropionate-Derived γ-Pyrone Natural Products

“…The route employed by Ward was a far more direct one, utilising an organocatalysed enantioselective aldol reaction of the readily available racemic aldehyde 147 with tetrahydrothiopyran-4-one (146). 37 The reaction proceeded with dynamic kinetic resolution to give adduct 148 in >98% ee. 38…”