Studies towards the total asymetric synthesis of macbecin
Studies towards the total asymetric synthesis of macbecin
The synthesis of (E)-3-iodo-2-methyl-2-propene-1-o1 (50) and (2S, 3S)-1-tert-butyldimethylsilyoxy-2,3-epoxybutane (35), required for the enantiospecific synthesis of the C-9 to C-18 fragmlent of macbecin, is described. The enantiospecific synthesis of (1R,2S)-(+)-1,4-dimethoxy-6-[1-methoxy-2-methyl-3-(phenylsulphonyl)propyl]-2-nitrobenzene (83) is also described. Model studies revealed that formation of the α-sulphonyl carbanion was only possible when the nitro group was reduced to an amine. The reactivity of the carbanion then varied with regards to the amine functionality as follows: R_2N-> RHN- > H_2N-. Diprotection was accomplished by incorporation of the amine into a 2,5-dimethylpyrrole system. Hence reaction of the α-sulphonyl carbanion of (1R,2S)-(+)-1-2,5-dimethoxy-3-[1-methoxy-2-methyl-3-(phenylsulphonyl)propyl]phenyl-2,5-dimethylpyrrole (116) with (2R,3R,2'R,3'S,6'S)-(4E)-5-(3',6'-dihydro-6'-methoxy-3'-methyl-2H-pyran-2'-yl)-3,5-dimethyl-2-methoxy-4-pentanal (46) should afford the C-9 to C-21 fragment of macbecin (84). Model desulphonation reactions are outlined which showed that oxidation of the adduct (84) to the β-ketosulphone (85) would be necessary to allow its conversion to (3S,4R,5S,7S,8R,2'R,3'S,6'S)-(1E)-1-(3',6'-dihydro-6'-methoxy-3'-methyl-2H-pyran-2'-yl)-8-[2,5-dimethoxy-3-(2,5-dimethylpyrrol-1-yl)-phenyl]-4,5,8-trimethoxy-1,3,7-trimethyl-1-octene (43). The conversion of (2R,3R)-(+)-methyl-3-(2,5-dimethoxy-3-nitrophenyl)-3-methoxy-2-methylpropionate (97) to (1R,2S)-(+)-1-[2,5-dimethoxy-3-(3-iodo-1-methoxy-2-methylpropyl)phenyl]-2,5-dimethylpyrrole (142) is described. Formation of the alkyllithium (141) from the iodide (142) was possible and this reacted with the enolizable aldehyde acrolein dimer to form 1-(3', 4' -dihydro-2H-pyran-2'-yl)-4-[2,5-dimethoxy-3-(2,5-dimethylpyrrol-1-yl)phenyl]-4-methoxy-3-methylbutan-1-ol (153). Thus a method for the construction of the C-18, C-19 bond of macbecin which avoids the problem of removal of an activating group was developed. (D73134/87)
University of Southampton
1986
Hayes, Jerome Francis
(1986)
Studies towards the total asymetric synthesis of macbecin.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
The synthesis of (E)-3-iodo-2-methyl-2-propene-1-o1 (50) and (2S, 3S)-1-tert-butyldimethylsilyoxy-2,3-epoxybutane (35), required for the enantiospecific synthesis of the C-9 to C-18 fragmlent of macbecin, is described. The enantiospecific synthesis of (1R,2S)-(+)-1,4-dimethoxy-6-[1-methoxy-2-methyl-3-(phenylsulphonyl)propyl]-2-nitrobenzene (83) is also described. Model studies revealed that formation of the α-sulphonyl carbanion was only possible when the nitro group was reduced to an amine. The reactivity of the carbanion then varied with regards to the amine functionality as follows: R_2N-> RHN- > H_2N-. Diprotection was accomplished by incorporation of the amine into a 2,5-dimethylpyrrole system. Hence reaction of the α-sulphonyl carbanion of (1R,2S)-(+)-1-2,5-dimethoxy-3-[1-methoxy-2-methyl-3-(phenylsulphonyl)propyl]phenyl-2,5-dimethylpyrrole (116) with (2R,3R,2'R,3'S,6'S)-(4E)-5-(3',6'-dihydro-6'-methoxy-3'-methyl-2H-pyran-2'-yl)-3,5-dimethyl-2-methoxy-4-pentanal (46) should afford the C-9 to C-21 fragment of macbecin (84). Model desulphonation reactions are outlined which showed that oxidation of the adduct (84) to the β-ketosulphone (85) would be necessary to allow its conversion to (3S,4R,5S,7S,8R,2'R,3'S,6'S)-(1E)-1-(3',6'-dihydro-6'-methoxy-3'-methyl-2H-pyran-2'-yl)-8-[2,5-dimethoxy-3-(2,5-dimethylpyrrol-1-yl)-phenyl]-4,5,8-trimethoxy-1,3,7-trimethyl-1-octene (43). The conversion of (2R,3R)-(+)-methyl-3-(2,5-dimethoxy-3-nitrophenyl)-3-methoxy-2-methylpropionate (97) to (1R,2S)-(+)-1-[2,5-dimethoxy-3-(3-iodo-1-methoxy-2-methylpropyl)phenyl]-2,5-dimethylpyrrole (142) is described. Formation of the alkyllithium (141) from the iodide (142) was possible and this reacted with the enolizable aldehyde acrolein dimer to form 1-(3', 4' -dihydro-2H-pyran-2'-yl)-4-[2,5-dimethoxy-3-(2,5-dimethylpyrrol-1-yl)phenyl]-4-methoxy-3-methylbutan-1-ol (153). Thus a method for the construction of the C-18, C-19 bond of macbecin which avoids the problem of removal of an activating group was developed. (D73134/87)
This record has no associated files available for download.
More information
Published date: 1986
Identifiers
Local EPrints ID: 460888
URI: http://eprints.soton.ac.uk/id/eprint/460888
PURE UUID: 9f11c2b0-9cf6-464d-8501-ab50b2062894
Catalogue record
Date deposited: 04 Jul 2022 18:31
Last modified: 04 Jul 2022 18:31
Export record
Contributors
Author:
Jerome Francis Hayes
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics