Patent GB-1508195-A (GB)
Title: Process for the manufacture of optically active cyclohexane derivatives
IPC: C07C401/00
Filed: 1975-08-20
Abstract: 1508195 Cyclohexane derivatives; carotenes F HOFFMANN-LA ROCHE & CO AG 20 Aug 1975 [21 Aug 1974 1 Nov 1974] 34605/75 Headings C2C C2V and C2P The invention comprises [6R]-2,2,6-trimethyl- 1,4-cyclohexanedione and [4R,6R]-4-hydroxy- 2,2,6 - trimethyl - cyclohexanone. The dione may be prepared by fermentatively hydrogenating ketoisophorone. The dione may be reduced to give the hydroxy cyclohexanone which may then be converted to an optically active carotenoid. Thus the hydroxy cyclohexanone is reacted with isopropenylmethyl ether to give [4R, 4<SP>1</SP>R] - 4,4<SP>1</SP> - (isopropylidenedioxy) - bis - {[6R] - 2,2,6 - trimethylcyclohexanone}, the product is reacted with but-3-yn-2-ol, the resulting 2 - hydroxy - 4 - {[4R,6R] - 1,4 - dihydroxy - 2,2,6 - trimethyl - cyclohex - 1 - yl} - but-3-yne is acetylated to give 2-acetoxy-4- {[4R,6R] - acetoxy - 1 - hydroxy - 2,2,6 - trimethylcyclohex - 1 - yl} - but - 3 - yne, said diacetate is dehydrated to give 2-acetoxy-4- {[4R] - 4 - acetoxy - 2,6,6 - trimethyl - cyclohex- 1 - en - 1 - yl} - but - 3 - yne and the acetylenic bond present is hydrogenated to an ethylenic bond, the resulting [3R]-3-hydroxy-#-ionol is converted by reaction with a triarylphosphonium halide or with a triaryl phosphine in the presence of a mineral acid into a 4-{[4R]-4- hydroxy - 2,6,6 - trimethyl - cyclohex - 1 - en - 1- yl} -but-3-ene-2-triarylphosphonium halide and this Wittig salt is condensed with l-acetoxy-3- methyl - hexa - 2,4 - dien - 6 - al to give [3R]- 3-hydroxy-retinyl acetate, the cis form obtained is converted into the trans form by isomerization, the one half of the [3R]-3-hydroxy-retinyl acetate is converted by reaction with a triarylphosphonium halide or with a triaryl phosphine in the presence of a mineral acid into a [3R]-3- hydroxy - retinyl - triarylphosphonium halide and the other half of the [3R]-3-hydroxy-retinyl acetate is saponified to give [3R]-3-hydroxyretinol and this alcohol is oxidized to give [3R]- 3 - hydroxy - retinal whereafter said [3R] - 3- hydroxy-retinyl-triarylphosphonium halide is either condensed with retinal or with [3R]-3- hydroxy-retinal to give [3R]-#-cryptoxanthin or [3R,31R] - zeaxanthin. Alternatively the Wittig salt 4 - {[4R] - 4 - hydroxy - 2,6,6 - trimethyl - cyclohex - 1 - en - 1 - yl} - but - 3 - ene- 2-triarylphosphonium halide is condensed with (a) 4,9 - dimethyl - dodeca - 2,4,8,10 - tetraen- 6-yne-1,12-dial and the resulting [3R,31R]- 15,15<SP>1</SP>-didehydro-zeaxanthin, after isomerization of cis form obtained to trans form, is converted by partial hydrogenation into [3R,3<SP>1</SP>R]- zeaxanthin, or (b) 4,9-dimethyl-dodeca-2,4,6,8, 10-pentaene-1,12-dial to give [3R,3<SP>1</SP>R]-zeaxanthin and cis form obtained is converted into trans form by isomerization. In a further alternative [3R]-3-hydroxy-#-ionol is converted by oxidation into [3R]-3-hydroxy-#-ionone, said ionone is reacted with an alkali metal acetylide to give [3R] - 3 - hydroxy - ethynyl - # - ionol, this latter compound is catalytically hydrogenated and the resulting [3R]-3-hydroxy-vinyl-#-ionol is converted by reaction with a triarylphosphonium halide or with a triarylphosphine in the presence of a mineral acid into a [3R]-3- hydroxy - # - ionylidenethyl - triaryl - phosphonium halide, said phosphonium halide is condensed with (a) 2,7-dimethyl-octa-2,4-dien-4- yne-1,10-dial and the resulting [3R,3<SP>1</SP>R]-15,15<SP>1</SP>- didehydro-zeaxanthin, after isomerisation of cis form obtained to trans form, is converted by partial hydrogenation into [3R,3<SP>1</SP>R]-zeaxanthin or (b) 2,7-dimethylocta - 2,4,6 - triene - 1,10 - dial to give [3R,3<SP>1</SP>R]-zeaxanthin and cis form obtained is converted into trans form by isomerization. In a further alternative the [3R]-3-hydroxy-#- ionylidenethyl-triaryl phosphonium halide is reacted with γ-acetoxytiglic aldehyde to give [3R]-3-hydroxy-retinyl acetate, cis form obtained is converted into trans form by isomerization, the one half of the [3R]-3-hydroxy-retinyl acetate is converted by reaction with a triarylphosphonium halide or with a triarylphosphine in the presence of a mineral acid into a [3R]-3- hydroxy - retinyl - triarylphosphonium halide and the other half of the [3R]-3-hydroxyretinyl acetate is saponified to give [3R]-3- hydroxy-retinol and this alcohol is oxidized to give [3R] - 3 - hydroxy - retinyl, whereafter said [3R] - 3 - hydroxy - retinyl - triarylphosphonium halide is either condensed with retinal or with [3R]-3-hydroxy-retinal to give [3R]-#- cryptoxanthin or [3R,3<SP>1</SP>R]-zeaxanthin. In a further alternative a [3R]-3-hydroxy-#-ionylidenethyl - triaryl - phosphonium halide is reacted with γ-acetoxy-tiglic aldehyde to give [3R]-3-hydroxy-retinyl acetate, said acetate is acetylated to give [3R]-3-acetoxy-retinyl acetate, cis form obtained is converted into trans form by isomerization, the one half of the [3R]-3- acetoxy-retinyl acetate is converted by reaction with a triarylphosphonium halide or with atriarylphosphine in the presence of a mineral acid into a [3R] - 3 - acetoxy - retinyl - triarylphosphonium halide and the other half of the [3R]-3- acetoxy-retinyl acetate is saponified to give [3R]-3-hydroxy-retinol and this alcohol is oxidized to give [3R]-3-hydroxy-retinal; whereafter said [3R] - 3 - acetoxy - retinyl - triarylphosphonium halide is reacted either with retinal or with [3R]-3-hydroxy-retinal to give [3R]-O-acetyl-#-cryptoxanthin or [3R,31R]- O-acetyl-zeaxanthin respectively and the latter compounds are saponified to give [3R]-#- cryptoxanthin or [3R,3<SP>1</SP>R]-zeaxanthin respectively. [3R]-Rubixanthin may be prepared by condensing a [3R]-3-hydroxy-retinyl-triarylphosphonium halide with γ-retinal. [3R]-#- Citraurin may be prepared by condensing a [3R] - 3 - hydroxy - retinyl - triarylphosphonium halide with 1,1 - diethoxy - 2,6 - dimethylocta - 2,4,6 - trien - 8 - al and saponifying the acetal obtained. [3R]-Reticulataxanthin may be prepared by condensing [3R]-#-citraurin with acetone.