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Asymmetric Syntheses of New Polyhydroxylated Quinolizidines: Cross‐Aldol Reactions of 7‐Oxabicyclo[2.2.1]heptan‐2‐one and 3a,4a,7a,7b‐Tetrahydro[1,3]dioxolo[4,5]furo[2,3‐ d ]isoxazole‐3‐carbaldehyde Derivatives
Author(s) -
Schaller Christophe,
Vogel Pierre
Publication year - 2000
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/(sici)1522-2675(20000119)83:1<193::aid-hlca193>3.0.co;2-i
Subject(s) - chemistry , isoxazole , bicyclic molecule , epimer , trimethylsilyl , stereochemistry , aldol reaction , ether , silyl ether , aldol condensation , lithium (medication) , steric effects , medicinal chemistry , silylation , organic chemistry , catalysis , medicine , endocrinology
The cross‐aldolization of (−)‐(1 S ,4 R ,5 R ,6 R )‐6‐ endo ‐chloro‐5‐ exo ‐(phenylseleno)‐7‐oxabicyclo[2.2.1]heptan‐2‐one ((−)‐ 25 ) and of (+)‐(3a R ,4a R ,7a R ,7b S )‐ ((+)‐ 26 ) and (−)‐(3a S ,4a S ,7a S ,7b R )‐3a,4a,7a,7b‐tetrahydro‐6,6‐dimethyl[1,3]dioxolo[4,5]furo[2,3‐ d ]isoxazole‐3‐carbaldehyde ((−)‐ 26 ) was studied for the lithium enolate of (−)‐ 25 and for its trimethylsilyl ether (−)‐ 31 under Mukaiyama 's conditions ( Scheme 2 ). Protocols were found for highly diastereoselective condensation giving the four possible aldols (+)‐ 27 (` anti '), (+)‐ 28 (` syn '), 29 (` anti '), and (−)‐ 30 (` syn ') resulting from the exclusive exo ‐face reaction of the bicyclic lithium enolate of (−)‐ 25 and bicyclic silyl ether (−)‐ 31 . Steric factors can explain the selectivities observed. Aldols (+)‐ 27 , (+)‐ 28 , 29 , and (−)‐ 30 were converted stereoselectively to (+)‐1,4‐anhydro‐3‐{( S )‐[( tert ‐butyl)dimethylsilyloxy][(3a R ,4a R ,7a R ,7b S )‐3a,4a,7a,7b‐tetrahydro‐6,6‐dimethyl[1,3]dioxolo[4,5]‐furo[2,3‐ d ]isoxazol‐3‐yl]methyl}‐3‐deoxy‐2,6‐di‐ O ‐(methoxymethyl)‐ α ‐ D ‐galactopyranose ((+)‐ 62 ), its epimer at the exocyclic position (+)‐ 70 , (−)‐1,4‐anhydro‐3‐{( S )‐[( tert ‐butyl)dimethylsilyloxy][(3a S ,4a S ,7a S ,7b R )‐3a,4a,7a,7b‐tetrahydro‐6,6‐dimethyl[1,3]dioxolo[4,5]furo[2,3‐ d ]isoxazol‐3‐yl]methyl}‐3‐deoxy‐2,6‐di‐ O ‐(methoxymethyl)‐ α ‐ D ‐galactopyranose ((−)‐ 77 ), and its epimer at the exocyclic position (+)‐ 84 , respectively ( Schemes 3 and 5 ). Compounds (+)‐ 62 , (−)‐ 77 , and (+)‐ 84 were transformed to (1 R ,2 R ,3 S ,7 R ,8 S ,9 S ,9a S )‐1,3,4,6,7,8,9,9a‐octahydro‐8‐[(1 R ,2 R )‐1,2,3‐trihydroxypropyl]‐2 H ‐quinolizine‐1,2,3,7,9‐pentol ( 21 ), its (1 S ,2 S ,3 R ,7 R ,8 S ,9 S ,9a R ) stereoisomer (−)‐ 22 , and to its (1 S ,2 S ,3 R ,7 R ,8 S ,9 R ,9a R ) stereoisomer (+)‐ 23 , respectively ( Schemes 6 and 7 ). The polyhydroxylated quinolizidines (−)‐ 22 and (+)‐ 23 adopt ` trans ‐azadecalin' structures with chair/chair conformations in which H−C(9a) occupies an axial position anti ‐periplanar to the amine lone electron pair. Quinolizidines 21 , (−)‐ 22 , and (+)‐ 23 were tested for their inhibitory activities toward 25 commercially available glycohydrolases. Compound 21 is a weak inhibitor of β ‐galactosidase from jack bean, of amyloglucosidase from Aspergillus niger , and of β ‐glucosidase from Caldocellum saccharolyticum . Stereoisomers (−)‐ 22 and (+)‐ 23 are weak but more selective inhibitors of β ‐galactosidase from jack bean.