Direct Enantioselective Organocatalytic Hydroxymethylation of Aldehydes Catalyzed by α,α-Diphenylprolinol Trimethylsilyl Ether

Boeckman, Robert K.; Miller, John R.

doi:10.1021/ol9017479

Cited by 53 publications

(46 citation statements)

References 29 publications

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“…33,34 The hydroxymethyl group was introduced via an aldol condensation with formaldehyde that was ultimately trapped as the silyl ether of the formacetal ( 11 ) using a chiral catalyst derived from proline. 35 Substituting Selectfluor ® for N -bromosuccinimide, which was used in the synthesis of the DOB precursor, to induce cyclization of 11 by oxidatively cleaving the 1,3-dithiane resulted in a significant improvement in yield, albeit as an inseparable mixture of diastereomers of 12 . 36 Two of the 4 diastereomers were separable upon desilylation to 4 .…”

Section: Resultsmentioning

confidence: 99%

Irreversible Inhibition of DNA Polymerase β by Small-Molecule Mimics of a DNA Lesion

et al. 2014

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Abasic sites are ubiquitous DNA lesions that are mutagenic and cytotoxic but are removed by the base excision repair pathway. DNA polymerase β carries out two of the four steps during base excision repair, including a lyase reaction that removes the abasic site from DNA following incision of its 5′-phosphate. DNA polymerase β is overexpressed in cancer cells and is a potential anticancer target. Recently, DNA oxidized abasic sites that are produced by potent antitumor agents were shown to inactivate DNA polymerase β. A library of small molecules whose structures were inspired by the oxidized abasic sites was synthesized and screened for their ability to irreversibly inhibit DNA polymerase β. One candidate (3a) was examined more thoroughly and modification of its phosphate backbone led to a molecule that irreversibly inactivates DNA polymerase β in solution (IC50 ~ 16 μM), and inhibits the enzyme’s lyase activity in cell lysates. A bis-acetate analogue is converted in cell lysates to 3a. The bis-acetate is more effective in cell lysates, more cytotoxic in prostate cancer cells than 3a, and potentiates the cytotoxicity of methyl methanesulfonate between 2- and 5-fold. This is the first example of an irreversible inhibitor of the lyase activity of DNA polymerase β that works synergistically with a DNA damaging agent.

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Section: Resultsmentioning

confidence: 99%

Irreversible Inhibition of DNA Polymerase β by Small-Molecule Mimics of a DNA Lesion

et al. 2014

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“…Worse results were achieved when aldehydes 55 bearing aromatic rings, oxygen, or other functionalities at the α-position were used in the hydromethylation process. This methodology was used as a key step for the synthesis of (−)-rasfonin [347].…”

Section: Aldehydes As Source Of Nucleophilementioning

confidence: 99%

Organocatalyzed Aldol Reactions

Guillena¹

2013

Modern Methods in Stereoselective Aldol Reactions

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The use of catalytic enantioselective methods to perform an aldol reaction provides a direct entry for the synthesis of chiral compounds and is probably the most attractive way to achieve this goal with high control of the chemo-, regio-, diastereo-, and enantioselectivity. The application of biochemical methods based on enzyme aldolases or antibodies, which are discussed in other chapters, avoid the use of preformed enolates or their equivalents for enhancing the global atom efficiency of the process [1] for which the narrow substrate scope is a major drawback. The discovery of methodologies to carry out the enantioselective direct aldol reaction [2] has eluded the production of stoichiometric by-products increasing the substrate scope. This task could be accomplished by using small molecules as catalysts, such as metal complexes (which are covered along this book) and organic molecules, also known as organocatalysts [3]. The growth of this last research area and the direct aldol reaction are closely linked [4], with the report on the use of (S)-proline as catalyst for the intermolecular aldol [5] definitely being the push for the development of the organocatalytic methods as a competitive methodology for the synthesis of chiral compounds.In a strict sense, an organocatalyzed reaction is a process in which all the involved reagents and catalysis are purely organic compounds of low-molecular weight, excluding boron-and silicon-containing derivatives. However, in some cases, the presence of a silyl group only plays a steric role and therefore can also be considered as an organocatalyzed process. Also, if the organocatalyst involved in a reaction is immobilized in a polymer, a dendrimer, or even an inorganic material that serves only as a support to facilitate its recovery [6], it could still be considered as an organocatalyst, although those types of derivatives have been scarcely used in the natural product synthesis and therefore will be excluded from this chapter. Therefore, a comprehensive overview of the direct aldol reaction [7], emphasizing the reactivity, scope, selectivity, and limitations of the methodology and giving several examples of their application to the synthesis of biologically active compounds, is discussed in this chapter.

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“…Though styrenyl-based substrates are known to have a preference for the branched regioisomer,11 α-substituted styrenes have been reported to be highly linear-selective 12. During the course of our studies we found that the branched aldehyde product is unstable to silica gel purification, and also dimerizes to a small extent to a cyclic acetal 13. To circumvent these problems we oxidize the unpurified reaction mixture directly and isolate the carboxylic acid product.…”

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confidence: 97%

Synthesis of Quaternary Carbon Centers via Hydroformylation

2010

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The application of hydroformylation to the synthesis of quaternary carbon centers is reported. The synthesis of the highly substituted carbon is achieved by applying a catalytic amount of 1. Ligand 1 serves as a catalytic directing group by covalently and reversibly binding to both the substrate and catalyst. The intramolecular nature of the directing group strategy accelerates the hydroformylation reaction such that the reaction is performed at mild temperatures (35–55 °C) and with excellent regioselectivity (b:l > 94:6).

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Direct Enantioselective Organocatalytic Hydroxymethylation of Aldehydes Catalyzed by α,α-Diphenylprolinol Trimethylsilyl Ether

Cited by 53 publications

References 29 publications

Irreversible Inhibition of DNA Polymerase β by Small-Molecule Mimics of a DNA Lesion

Irreversible Inhibition of DNA Polymerase β by Small-Molecule Mimics of a DNA Lesion

Organocatalyzed Aldol Reactions

Synthesis of Quaternary Carbon Centers via Hydroformylation

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