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Wieland–Miescher ketone

About: Wieland–Miescher ketone is a(n) research topic. Over the lifetime, 88 publication(s) have been published within this topic receiving 938 citation(s). The topic is also known as: 8a-Methyl-3,4,7,8-tetrahydro-2H-naphthalene-1,6-dione.

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TL;DR: First time, for the first time, the one-step alkylation of dimedone and 1,3-cyclohexanedione with aldehydes and Hantzsch ester is developed through an organocatalytic reductiveAlkylation strategy.
Abstract: A practical and novel organocatalytic chemo- and enantioselective process for the cascade synthesis of highly substituted 2-alkyl-cyclohexane-1,3-diones and Wieland−Miescher (W−M) ketone analogs is presented via reductive alkylation as a key step. First time, we developed the one-step alkylation of dimedone and 1,3-cyclohexanedione with aldehydes and Hantzsch ester through an organocatalytic reductive alkylation strategy. Direct combination of l-proline-catalyzed cascade Knoevenagel/hydrogenation and cascade Robinson annulation of CH acids (dimedone and 1,3-cyclohexanedione), aldehydes, Hantzsch ester, and methyl vinyl ketone furnished the highly functionalized W−M ketone analogues in good to high yields and with excellent enantioselectivities. Many of the reductive alkylation products show a direct application in pharmaceutical chemistry.

163 citations

Journal ArticleDOI
Abstract: It has been said that the active components in the Digitalis extracts have been “the most ingested drugs in medicine”.1 These substances, usually called cardenolides, differ from ordinary steroids in three major respects: the C/D ring system is cis rather than trans fused, there is a tertiary hydroxyl at C-14, and the substituent at C-17 (a butenolide) is in the thermodynamically less stable â orientation.2 As might be expected, many partial syntheses of cardenolides have been described starting with readily available steroids.3,4 We now report the total synthesis of natural (+)-digitoxigenin (1), the biologically active cardenolide which, as its trisaccharide derivative digitoxin, is one of the most frequently used of the active principles isolated from Digitalis species. We divided the synthesis, which we carried out both to racemic and to natural (+)-digitoxigenin, in three parts: synthesis of the tricyclic enone 2; elaboration of the fused 5-membered ring D to produce a tetracyclic system bearing both a 14-â-hydroxy substituent and a substituent at C-17 capable of further transformation; and, finally, elaboration of that substituent to the â-oriented butenolide system. We chose to approach the construction of the tricyclic enone 2 via an intramolecular [4 + 2] cycloaddition, as schematized in Figure 1. We initiated the synthesis from the monoketal (-)-3, prepared by applying to the readily available (S)-enantiomer of the Wieland Miescher ketone,5 the sequence previously described6 using its racemate. Ozonolysis of the trimethylsilyl enol ether of 3 gave, in a not unprecedented reaction,7 a mixture of R-hydroxy ketones which was reduced (NaBH4) to the corresponding glycols, followed by cleavage with periodate to the dialdehyde 4 (71% overall yield from 3). The two aldehyde groups in 4 now had to be differentially elaborated.

75 citations

Journal ArticleDOI
Abstract: This research was supported by the Ministerio de Ciencia e Innovacion (Spain)-FEDER through projects CTQ2007- 61338/BQU, CTQ2007-62771/BQU and Consolider Ingenio 2010 CSD2007-00006. Thanks are also due to the Comissionat per a Universitats i Recerca (Catalonia) for Grant 2005SGR-00442, Generalitat Valenciana for Grant (GVPRE/ 2008/006) and the University of Alicante (GRJ06-05).

48 citations

Journal ArticleDOI
Abstract: The preparation through Robinson annulation of enantiopure building blocks with both academic and industrial relevance, such as the Wieland–Miescher and Hajos–Parrish ketones, has suffered from important drawbacks, such as the need for high catalyst loading or extremely long reaction times. Here we report a heterogenized organocatalyst based on Luo’s diamine for fast and broad-scope enantioselective Robinson annulation reactions. The polystyrene-supported diamine 19a enables the high-yield, highly enantioselective preparation of a wide range of chiral bicyclic enones under mild conditions, with reaction times as short as 60 min (batch) or residence times of 10 min (flow). In contrast with its homogeneous counterpart 19b, the catalytic resin 19a experiences a notable increase in catalytic activity with temperature in 2-MeTHF (a 10-fold decrease in reaction times without erosion in enantioselectivity is observed from room temperature to 55 °C). The scope of the transformation in batch mode has been illustra...

42 citations

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