An expeditious synthesis of tamoxifen, a representative SERM (selective estrogen receptor modulator), via the three-component coupling reaction among aromatic aldehyde, cinnamyltrimethylsilane, and beta-chlorophenetole.
Two new synthetic pathways to the anti-cancer agent tamoxifen and its derivatives were developed. The first route involved the aldol reaction of benzyl phenyl ketone with acetaldehyde followed by Friedel-Crafts substitution with anisole in the presence of Cl(2)Si(OTf)(2) to produce 1,1,2-triaryl-3-acetoxybutane, a precursor of the tamoxifen derivatives. The second one utilized the novel three-component coupling reaction among aromatic aldehydes, cinnamyltrimethylsilane, and aromatic nucleophiles using HfCl(4) as a Lewis acid catalyst to produce 3,4,4-triarylbutene, that is also a valuable intermediate of the tamoxifen derivatives. The former strategy requires a total of 10 steps from the aldol formation to the final conversion to tamoxifen, whereas the latter needs only three or four steps to produce tamoxifen and droloxifene including the installation of the side-chain moiety and the base-induced double-bond migration to form the tetra-substituted olefin structure. This synthetic strategy seems to serve as a new and practical pathway to prepare not only the tamoxifen derivatives but also the other SERMs (selective estrogen receptor modulators) including estrogen-dependent breast cancer and osteoporosis agents.
Shiina
Isamu
I
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
Sano
Yoshiyuki
Y
Nakata
Kenya
K
Suzuki
Masahiko
M
Yokoyama
Toshikazu
T
Sasaki
Akane
A
Orikasa
Tomoko
T
Miyamoto
Tomomi
T
Ikekita
Masahiko
M
Nagahara
Yukitoshi
Y
Hasome
Yoshimune
Y
D000447:Aldehydes / Q000737:chemistry*; D024322:Amino Acids, Aromatic / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D010647:Phenyl Ethers / Q000737:chemistry*; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013629:Tamoxifen / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors; D014297:Trimethylsilyl Compounds / Q000737:chemistry*
D000447:Aldehydes; D024322:Amino Acids, Aromatic; D000970:Antineoplastic Agents; D002934:Cinnamates; D010647:Phenyl Ethers; D020845:Selective Estrogen Receptor Modulators; D014297:Trimethylsilyl Compounds; C526468:cinnamyltrimethylsilane; D013629:Tamoxifen; C079413:phenetole