Wieland-Miescher ketone

Chembox new
Reference= [ [http://www.sigmaaldrich.com/catalog/search/ProductDetail/ALDRICH/M65157?cm_mmc=PubChem-_-public%20database-_-products-_-products (±)-8a-Methyl-3,4,8,8a-tetrahydro-1,6(2H,7H)-naphthalenedione] at Sigma-Aldrich]
ImageFile=Wieland-Miescherketone.svg
ImageSize=120px
IUPACName=8a-Methyl-3,4,7,8-tetrahydro-2"H"-naphthalene-1,6-dione
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Section1= Chembox Identifiers
CASNo=20007-72-1
PubChem=89262
SMILES=CC12CCC(=O)C=C1CCCC2=O
Section2= Chembox Properties
Formula=C₁₁H₁₄O₂
MolarMass=178.23 g/mol
Appearance=
Density=
MeltingPt=47-50 °C
BoilingPt=
Solubility=
Section3= Chembox Hazards
MainHazards=
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The Wieland-Miescher ketone [Wieland, P.; Miescher, K. "Über die Herstellung mehrkerniger Ketone.", "Helv. Chim. Acta" 1950, "33", 2215. DOI|10.1002/hlca.19500330730] is a bicyclic di-ketone (enedione) and is a versatile synthon which has so far been employed in the total synthesis of more than 50 natural products, predominantly sesquiterpenoids, diterpenes and steroids possessing possible biological properties including anticancer, antimicrobial, antiviral, antineurodegenerative and immunomodulatory activities. The reaction is named after two chemists from Ciba Geigy, Karl Miescher and Peter Wieland (not to be confused with Heinrich Otto Wieland). Examples of syntheses performed using this ketone as a starting material are that of ancistrofuran [Ciceri, Paola, Demnitz, F.W. Joachim, Souza, Márcia C.F. de, Lehmanna, Maik. "A Common Approach to the Synthesis of Monocyclofarnesyl Sesquiterpenes". "J. Braz. Chem. Soc." 1998, "9", 409-414. ISSN 0103-5053. ( [http://www.scielo.br/scielo.php?pid=S0103-50531998000400015&script=sci_arttext&tlng=en Article] )] and in the Danishefsky Taxol total synthesis.

Most advances in total synthesis methods starting from Wieland-Miescher ketone were fueled by the search for alternative methods for the industrial synthesis of contraceptive and other medicinally relevant steroids, an area of research that flourished in the 1960s and 1970s. [Wiechert, R. "The Role of Birth Control in the Survival of the Human Race". "Angew. Chem. Int. Ed." 1977, "16", 506-513.] Wieland-Miescher ketone contains the AB-ring structure of steroids and is for this reason an attractive starting material for the steroid skeleton, an approach used in one successful synthesis of adrenosterone. [Dzierba, C. D.; Zandi, K. S.; Moellers, T.; Shea, K. J. "An Ascending Synthesis of Adrenalcorticosteroids. The Total Synthesis of (+)-Adrenosterone". "J. Am. Chem. Soc." 1996, "118", 4711-4712.]

The original Wieland-Miescher ketone is racemic and prepared in a Robinson annulation of 2-methyl-1,3-cyclohexanedione and methyl vinyl ketone. The intermediate alcohol is not isolated. [Wieland-Miescher synthesis: a) water, acetic acid, hydroquinone (stabilizes EVK) b)L-proline, DMSO d) hydrogen , Raney nickel, sodium hydroxide e) methyl iodide, dioxane. specific rotation 68°.] The required 2-methyl-1,3-cyclohexanedione can be prepared from resorcinol [A. B. Mekler, S. Ramachandran, S. Swaminathan, and Melvin S. Newman Organic Syntheses, Coll. Vol. 5, p.743 (1973); Vol. 41, p.56 (1961). ( [http://www.orgsyn.org/orgsyn/prep.asp?prep=cv5p0743 Article] )] by hydrogenation over Raney nickel to dihydroresorcinol as the enolate followed by alkylation with methyl iodide.

An enantioselective synthesis employs L-proline as a chiral auxiliary in catalytic amounts: [1,6(2H, 7H)-Naphthalenedione, 3,4,8,8a-tetrahydro-8a-methyl-, (S)- Paul Buchschacher, A. Fürst, and J. Gutzwiller Organic Syntheses, Coll. Vol. 7, p.368 (1990); Vol. 63, p.37 (1985). ( [http://www.orgsyn.org/orgsyn/prep.asp?prep=cv7p0368 Article] )]

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This reaction appeared in 1971 in the patent literature by Z. G. Hajos and D. R. Parrish. In this patent, the isolation and characterization of the above pictured optically active intermediate bicyclic ketol (in parenthesis above) has also been described, because they worked at ambient temperature in anhydrous dimethylformamide (DMF) solvent. Working in DMSO solvent does not allow isolation of the bicyclic ketol intermediate, it leads directly to the optically active bicyclic dione. [ Z. G. Hajos, D. R. Parrish, German Patent DE 2102623 (29 July 1971) and USP 3,975,440 (Aug.17, 1976) Example 21.] The reaction is called the Hajos-Parrish reaction or the Hajos-Parrish-Eder-Sauer-Wiechert reaction. [1 H-Indene-1,5(6 H)-dione, 2,3,7,7a-tetrahydro-7a-methyl-, (S)- Zoltan G. Hajos and David R. Parrish Organic Syntheses, Coll. Vol. 7, p.363 (1990); Vol. 63, p.26 (1985) [http://www.orgsynth.org/orgsyn/prep.asp?prep=cv7p0363 Article] Identical reaction with 2-methyl-1,3-cyclopentanedione (5 membered ring instead of a 6 membered ring) ] .

This reaction has also been performed in a one-step procedure: ["A proline-catalyzed asymmetric Robinson annulation reaction" Tetrahedron Letters, Volume 41, Issue 36, September 2000, Pages 6951-6954 Tommy Bui and Carlos F. Barbas doi|10.1016/S0040-4039(00)01180-1]

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