Asymmetric Synthesis of Hexapropionate Synthons by Sequential Enantiotopic Group Selective Enolization of Meso Diketones

Ward, Dale E.; Gillis, H. Martin; Akinnusi, Olukayode T; Rasheed, M. Abdul; Saravanan, K.; Sasmal, Pradip K.

doi:10.1021/ol060802k

Cited by 16 publications

(8 citation statements)

References 24 publications

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“…Initially, we attempted to optimize the preparation of (±)-5a using (±)-4 (Table 3). 22 Sonication 23 did not improve our previously optimized conditions (1 M in DMSO) and reactions without solvent 23b,24 did not proceed at 22°C (<10% conversion in 1 d). However, excellent results were obtained under solvent-free conditions by sonication of the mixture at 38°C (Table 3, entry 1).…”

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confidence: 82%

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

Ward¹,

Jheengut²,

Beye³

et al. 2011

Synlett

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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...

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confidence: 82%

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

Ward¹,

Jheengut²,

Beye³

et al. 2011

Synlett

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“…This strategy was successfully demonstrated by Ward et al . in the Diels–Alder reactions of thiopyran dienes as useful surrogates for unreactive terminally cis substituted dienes and in tandem aldol reactions of thiopyranones to access polypropionate building blocks .…”

Section: Introductionmentioning

confidence: 99%

Antiselective Three‐Component Mannich Reactions in Thiopyran‐4‐one System

Abaee

Mojtahedi

Akbari

et al. 2012

Journal of Heterocyclic Chem

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The one‐pot, three‐component Mannich reactions of thiopyran‐4‐one 1 with different aromatic aldehydes and aniline derivatives in the presence of catalytic quantities of ZrOCl2.8H2O (15 mol %) led to rapid and high yield formation of various 3‐methylamino substituted derivatives of 1 at room temperature. Spectroscopic and X‐ray analyses of the products suggested the formation of the anti stereoisomers as the major product of the reactions.

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“…We also explored aldol reactions of 4 with the meso dialdehyde 62a (Scheme 13). 47 Reaction of the 'amine-free' lithium enolate 67a with 62a gave only the monoaldol adduct (AE)-69 even when using an excess of 67a. The reaction was highly diastereoselective (Felkin addition to 67a with anti relative topicity) in analogy to the reaction of 4 with 54 (Table 1, entry 2).…”

Section: Diastereoselective Reactionsmentioning

confidence: 99%

“…Scheme 13 Aldol reactions of 4 with 62a. 47 reaction of 62a with 67b (1.2 equiv.) also gave (AE)-69 along with a trace of the bisaldol 68.…”

Section: Diastereoselective Reactionsmentioning

confidence: 99%

“…92 The meso bisaldol adducts 99a and 68 were converted into meso 1,9-diketones 117-119 as shown in Scheme 28. 47 Under optimized conditions, reactions of the diketones 117-119 with the well-known chiral lithium amide base 120 in the presence of Me 3 SiCl produced the corresponding mono enol ethers 121-123 in good yields and with excellent enantioselectivities. Control experiments showed that the observed enantiopurities were conversion dependent due to a concomitant kinetic resolution in the formation of the corresponding bis enol ethers (meso); the latter were readily recycled by conversion to the starting diketones.…”

Section: Syntheses Of Siphonarin B Baconipyrone a And Baconipyrone C ...mentioning

confidence: 99%

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The thiopyran route to polypropionates

Ward

2011

Chem. Commun.

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The strategic use of thiopyran templates to facilitate polypropionate synthesis was first demonstrated in Woodward's landmark total synthesis of erythromycin A in 1981 where the topology of a fused bicyclic system was exploited. In the ensuing three decades, various alternative strategic applications of thiopyran motifs to achieve key stereoselective transformations have emerged including, inter alia, unique substrates for chemoenzymatic syntheses, surrogates for 3-pentanone in enantioselective aldol reactions, and templates for enantiotopic group selective reactions. This review summarizes these developments.

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Asymmetric Synthesis of Hexapropionate Synthons by Sequential Enantiotopic Group Selective Enolization of Meso Diketones

Cited by 16 publications

References 24 publications

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

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

Antiselective Three‐Component Mannich Reactions in Thiopyran‐4‐one System

The thiopyran route to polypropionates

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