Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
  • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
  • C07J1/0051—Estrane derivatives
  • C07J1/0055—Estrane derivatives not substituted in position 17
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
  • C07J1/0051—Estrane derivatives
  • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
  • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
  • C07J1/0077—Ethers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00

Definitions

• the invention relates to bissteroidal compounds and their use for the preparation of chiral complexes, useful as catalysts for various asymmetric syntheses.
• the present invention describes the diastereoselective synthesis of (Fta)- and (Sa)- 4,4'-bis(3-Diphenylphosphinoestra-1 ,3,5(10), 6, 8-pentaene) and the application of these new bisphosphines as chiral ligands in metal complexes for the enantioselective hydrogenation of ⁇ -ketoesters, ⁇ - ⁇ -unsaturated acids and dehydroaminoacids.
• Detailed description of the invention are examples of the invention.
• Rl stands for hydrogen, alkyl, acyl, fluorine, and X-1 R5, where X-
• R2 stands for hydrogen and alkyl; the stereochemistry of C-13, C-14 and C-17 may either be a or b,
• X stands for oxygen, hydroxyl, trifluormethylsulfonyloxy, or (R 6 ) 2 P, where Rg can be aryl, alkyl and cycloalkyl,
• R3 stands for hydrogen, alkyl, aryl, trialkylsilyl, fluorine and X2R6.
• X 2 stands for oxygen and sulfur and
• Rg stands for hydrogen, trifluormethylsulfonyl, alkyl, cyloalkyl or aryl.
• R4 can either be a substituent in the 6 or 7 position of the steroid with the meaning of hydrogen, alkyl, aryl, fluorine, and X3R7, where X3 stands for oxygen, sulfur or trialkylsilyl and R7 stands for hydrogen, trifluormethylsulfonyl, alkyl or aryl, and the B-ring of the steroid contains none or two double bonds.
• the alkyl radical of Ri - R7 have the meaning of lower alkyl substituents, for example the methyl-, ethyl-, propyl-, 2-methylethyl-, 2-methyl-propyl-, 3-methyl-propyl-, 2,2- dimethyl-ethyl- or butyl group.
• the acyl radical of Ri have the meaning of C1-C6- groups, per example acyl-, propionylic-, butyric or hexanoic group.
• the aryl group radical of R3, R4, R$, Rg and R7 have the meaning of phenyl-, benzyl- or 4-methyl- phenyl substituents.
• the cycloalkyl radical of Rg has the meaning of a cyclopentyl- or cyclohexyl group.
• the trialkylsilyl radical of R3 or X3 have the meaning of trimethyl- or tert.-butyldimethylsilyl.
• the targets (Ra)- and (Sa)-4,4'-bis(Estra-1 , 3,5(10),6,8-pentaen-3-ol) (bisequilenol) 3 are prepared from Estra-1 , 3,5(10) ,6, 8-pentaen-3-ol 2 via metal catalyzed phenolic coupling.
• the coupling is performed with catalytic amounts of a copper-amine complex in methylenechloride under an oxygen atmosphere (Tetrahedron Lett. 1994, 35, 7983). generating the diastereomers S-3 and R-3.
• the diastereoselectivity of the coupling shows a temperature dependance favouring the R-isomer at room temperature with a diasteromeric excess of 50%. At lower temperature the selectivity is inverted, favouring the S-isomer with almost the same diasteromeric excess (Table 1). In order to make both isomers available the coupling is performed at 0° C providing both diastereomers in a combined yield of 92-96%.
• the absolute configuration of the reduction products is also the same as in the Noyori reduction. As expected the reduction with the two diasteromeric ligands R-3 and S-3 produce the opposite enantiomers of the reduction product.
• the bissteroids R-/S-4 and R-/S-5 were prepared by copper mediated coupling
• the catalysts R-Ti-1 and S-Ti-1 afford the product 3-Methoxyestra- 1 , 3,5(10),8,14-pentaene-17-one due to their diastereomeric nature with a different chemical and optical yield each.
• the triflate 6 was then converted into the bisphoshine 7 without any isomerisation of the diastereomers in 83% yield.
• epimeric phosphines Epi-R-7 and Epi-S-7 are available according to a similar synthetic sequence starting with 14-Epi-equilenine 14-Epi-1 (Tetrahedron Lett. 1971 ,
• the new phosphines R-7 and S-7 were tested as chiral ligands in a ruthenium complex for the asymmetric hydrogenation of methyl-acetoacetate, N-acetyl-cinnamic acid and tiglic acid as representative examples (Table 3).
• the chiral ruthenium complex is prepared by heating the bisphosphines R-/S-7 with [RuCI 2 (benzene)] 2 in DMF (Tetrahedron Lett. 1991 , 32, 4163).
• the new chiral complexes synthesized from [RuCI 2 (benzene)] 2 and the bissteroidal ligands 7 are more powerful than the state-of-the-art BINAP-ruthenium complexes of Noyori as they are of broader applicability and allow the preparation of a range of substrates of extraordinary high enantiomeric purity in a quantitative yield.
• the new bissteroidal ligands 3-5 have proven to be highly effective for the enantioselective reduction of ketones exemplified by the reduction of acetophenone and to be highly effective chiral lewis acids exemplified by the enantioselective cyclization of methyl-secone.
• a dry 50 ml Schlenk tube containing a Teflon coated stirring bar was charged with solution of UAIH4 in THF (1. 5 ml, 0.98 M) and then a solution of ethyl alkohol in THF (0.9 ml, 1.7 M) was added dropwise for a period of ca. 10 min. Subsequently a THF solution of R-4 (3 ml, 0.53 M) was added dropwise for a period of 30 min. After stirring for additional 30 min. at room temperature the reducing agent was cooled to -90°C. A solution of acetophenone (0.45 ml, 0.7 M) in THF was added slowly (for a period of 20 min).

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Steroid Compounds (AREA)

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• 1996
  • 1996-12-20 EP EP96250295A patent/EP0849274A1/de not_active Withdrawn
• 1997
  • 1997-12-18 JP JP52834798A patent/JP2001506663A/ja active Pending
  • 1997-12-18 CA CA002275879A patent/CA2275879A1/en not_active Abandoned
  • 1997-12-18 EP EP97954819A patent/EP0946583A1/de not_active Withdrawn
  • 1997-12-18 AU AU62057/98A patent/AU6205798A/en not_active Abandoned
  • 1997-12-18 WO PCT/EP1997/007098 patent/WO1998028322A1/en not_active Application Discontinuation

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