Total syntheses of (+/-)-ovalicin, C4(S *)-isomer, and its C5-analogs and anti-trypanosomal activities.
Total syntheses of (+/-)-ovalicin, its C4(S( *))-isomer 44, and C5-side chain intermediate 46 were accomplished via an intramolecular Heck reaction of (Z)-3-(tert-butyldimethylsilyloxy)-1-iodo-1,6-heptadiene and a catalytic amount of palladium acetate. Subsequent epoxidation, dihydroxylation, methylation, and oxidation led to (3S( *),5R( *),6R( *))-5-methoxy-6-(tert-butyldimethylsilyloxy)-1-oxaspiro[2.5]octan-4-one (2), a reported intermediate. The addition of a side chain with cis-1-lithio-1,5-dimethyl-1,4-hexadiene (27) followed by oxidation afforded (+/-)-ovalicin. The functional group manipulation afforded a number of regio- and stereoisomers, which allow the synthesis of analogs for bioevaluation. The structure of 44 was firmly established via a single-crystal X-ray analysis. The stereochemistry at C4 generated from the addition reactions of alkenyllithium with ketones 2, 40, and 45 is dictated by C6-alkoxy functionality. Anti-trypanosomal activities of various ovalicin analogs and synthetic intermediates were evaluated, and C5-side chain analog, 46, shows the strongest activity. Compound 44 shows antiproliferative effect against HL-60 tumor cells in vitro. Compounds 46 and a precursor, (3S( *),4R( *),5R( *),6R( *))-5-methoxy-4-[(E)-(1',5'-dimethylhexa-1',4'-dienyl)]-6-(tert-butyldimethylsilyloxy)-1-oxaspiro[2.5]octan-4-ol (28), may be explored for the development of anti-parasitic drugs.
Hua
Duy H
DH
Department of Chemistry, Kansas State University, Manhattan, KS 66506-3701, USA. duy@ksu.edu
Zhao
Huiping
H
Battina
Srinivas K
SK
Lou
Kaiyan
K
Jimenez
Ana L
AL
Desper
John
J
Perchellet
Elisabeth M
EM
Perchellet
Jean-Pierre H
JP
Chiang
Peter K
PK
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D006900:Hydroxylation; D008745:Methylation; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D021261:Parasitic Sensitivity Tests; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
D000981:Antiprotozoal Agents; D004852:Epoxy Compounds; D012717:Sesquiterpenes; C002781:ovalicin