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

Abstract

Aldol reactions of racemic enolizable dioxolan-protected a-substituted-b-ketoaldehydes with representative achiral ketones catalyzed by proline or 5-(2-pyrrolidine-2-yl)-1H-tetrazole in wet DMSO proceed with dynamic kinetic resolution (or via DYKAT with an a-substituted-b-alkoxyaldehyde) to give adducts with high dr and ee.The first examples of proline-catalyzed enantioselective direct intermolecular aldol reactions were reported in a landmark paper by List, Lerner, and Barbas in 2000. 1 In the ensuing decade, this reaction has been extensively studied by numerous research groups, and remarkable progress has been achieved. 2 Despite the impressive stereoselectivity that has been obtained in many examples and with diverse organocatalysts, a continuing limitation to synthetic applications of this process has been the rather narrow substrate scope; that is, few competent ketone donors and mainly simple achiral or aromatic aldehyde acceptors. Our interest in this process stemmed from its possible application to our thiopyran-based synthetic route to polypropionates via stereoselective sequential two-directional aldol reactions of 1 and 2a (Scheme 1). 3 Scheme 1 Proline-catalyzed reaction of 1 with (±)-2a via DKR 8aIn a preliminary study, we established that proline-catalyzed aldol reactions of 1 with simple achiral aldehydes in DMF or DMSO (with controlled amounts of water) are highly diastereo-and enantioselective. 4 This was significant because 3-pentanone is a poor substrate in prolinecatalyzed aldol reactions. 2 Among the scattered examples of proline-catalyzed aldol reactions of chiral aldehydes, 5 generally moderate levels of enantiotopic group selectivity 6 (or double stereodifferentiation) 7 were observed. Nonetheless, we reasoned that because of its near exclusive Felkin diastereoface selectivity, racemic aldehyde (±)-2a would be a good candidate to undergo proline-catalyzed direct aldol with 1 with high enantiotopic group selectivity (i.e., kinetic resolution 6 ). 8 Under optimized conditions, (-)-5a was obtained essentially as a single stereoisomer in a process that proceeded via dynamic kinetic resolution (DKR, 9 Scheme 1). 8 In this paper, we report the extension of this concept to other ketones and aldehydes and simple procedures for the preparation of 5a on >30 gram scale.We next investigated the efficacy of the more soluble catalyst 6. 10 Aldol reactions of 1 with (±)-2a, benzaldehyde (2c), and isobutyraldehyde (2d) catalyzed by 6 (0.2 equiv) were conducted under the conditions previously optimized using 4 (0.5 equiv) revealing that 6 was the superior catalyst for the reactions with (±)-2a and 2c, (Table 1; cf. entries 1, 2, 4, 5, and 7, 8). The individual reactions were optimized by examining the effects of various reaction parameters including the amount of added water, 4 stoichiometry, catalyst loading, and reaction time. A solvent screen revealed that DMF was superior for 2c and DMSO for 2d and (±)-2c. 11 The addition of controlled amounts of water improved all reactions and the adducts 5a, 5c...

On the Origin of Siphonariid Polypropionates: Total Synthesis of Caloundrin B and Its Isomerization to Siphonarin B

“…The proposed use of the racemic fragment (±)-30 for this strategy would require studies of methodology on the design of aldol reactions that proceed with kinetic resolution (vide infra). On the other hand, the stereoselective synthesis of the trioxaadamantane fragment using the thiopyran route to polypropionates 29,40 was envisaged.…”

The thiopyran route to polypropionates

“…12b,c Enantioselective reductions of methyl tetrahydro-4oxo-2H-thiopyran-3-carboxylate (3) and related 1,3-dicarbonyl derivatives Synthesis of anhydroserricornin Whereas Baker's yeast reduction of methyl 2-methyl-3oxopentanoate (24) produces anti methyl (2R,3R)-2-methyl-3-oxopentanoate (25) with low enantioselectivity, 16 similar reduction of the thiopyran analogue 3 gives the syn diastereomer 26 with high ee especially in the presence of DMSO. 17, 18 Hoffmann et al 17 took advantage of this simple access to highly enantioenriched (+)-26a in enantioselective syntheses of anhydroserricornin (31), a sex pheromone of the female cigarette beetle (Lasioderma serricorne F.), 19 and (3S,4S)-4methyl-3-heptanol (34), an aggregation pheromone of bark beetles (Scolytus scolytus and S. multistriatus) 20 (Scheme 3). In a series of straightforward steps, 26a was converted into iodide 27, an intermediate in Mori's synthesis of serricornin.…”

“…29 Relative configurations were assigned by NMR but data were not reported. Potential application of this approach to the synthesis of polypropionate stereotriads was demonstrated by NaBH 4 reduction of the benzaldehyde adduct (AE)-48d followed by RANEY s nickel desulfurization of the resulting (AE)-50 to Scheme 3 Hoffmann's syntheses of pheromones anhydroserricornin (31) and (3S,4S)-4-methyl-3-heptanol (34). 17…”

Correction to “Enantioconvergent Synthesis of Functionalized γ-Butyrolactones via (3 + 2)-Annulation”

“…Soc. 2012 , 134 , 7329–7332.” The references shown as ref ( 1 ) below should then follow as refs 4b–e.…”