Catalyst-controlled asymmetric synthesis of fostriecin and 8-epi-fostriecin.
Catalytic asymmetric synthesis of the natural antibiotic fostriecin (CI-920) and its analogue 8-epi-fostriecin and evaluation of their biological activity are described. We used four catalytic asymmetric reactions to construct all of the chiral centers of fostriecin and 8-epi-fostriecin; cyanosilylation of a ketone, Yamamoto allylation, direct aldol reaction, and Noyori reduction, two of which were developed by our group. Catalytic enantioselective cyanosilylation of ketone 13 produced the chiral tetrasubstituted carbon at C-8. Both enantiomers of the product cyanohydrin were obtained with high enantioselectivity by switching the center metal of the catalyst from titanium to gadolinium. Yamamoto allylation constructed the C-5 chiral carbon in the alpha,beta-unsaturated lactone moiety. A direct catalytic asymmetric aldol reaction of an alkynyl ketone using LLB catalyst constructed the chirality at C-9 with the introduction of a synthetically versatile alkyne moiety, which was later converted to cis-vinyl iodide, the substrate for the subsequent Stille coupling for the triene synthesis. Noyori reduction produced the secondary alcohol at C-11 from the acetylene ketone 6 with excellent selectivity. Importantly, all the stereocenters were constructed under catalyst control in this synthesis. This strategy should be useful for rapid synthesis of stereoisomers of fostriecin.
Maki
Keisuke
K
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Japan.
Motoki
Rie
R
Fujii
Kunihiko
K
Kanai
Motomu
M
Kobayashi
Takayasu
T
Tamura
Shinri
S
Shibasaki
Masakatsu
M
D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry; D002384:Catalysis; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D015394:Molecular Structure; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D011090:Polyenes; D011753:Pyrones; D013302:Streptomyces / Q000737:chemistry
D000475:Alkenes; D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D011090:Polyenes; D011753:Pyrones; D010749:Phosphoprotein Phosphatases; C040313:fostriecin