NEWS OF THE WEEK ORGANIC
SYNTHESIS
THIOSTREPTON FROM SCRATCH First total synthesis of complex antibiotic with unusual mechanism
T
HIOSTREPTON, AN EXTRA-
ordinarily complex bacter ial natural product that's used as a topical veterinary an tibiotic and also has promising antimalarial and anticancer ac tivity, has yielded to total chemi cal synthesis. First isolated from bacteria in 1955, thiostrepton has an unusu al type of antibiotic activity: It disables protein biosynthesis by binding to ribosomal RNA and one of its associated proteins. British crystallographer and 1964 Nobel Prize winner Dorothy Crowfoot Hodgkin solved the structure in 1970. Thiostrepton includes 10 rings, 11 peptide bonds, extensive unsaturation, and 17 stereogenic cen ters. More challenging still, it is highly acid- and base-sensitive. It's the parent compound and the most complex member of a fam ily of thiopeptide antibiotics. Now, the compound has suc cumbed to the synthetic bland ASIA-PACIFIC
This key step helps validate a 1978 proposal that bacteria use this kind of reaction to biosynthesize thiopeptide antibiotics. Nicolaou and coworkers in corporated the dehydropiperi dine into the thiazoline-containing macrocycle. They combined that macrocycle with a quinaldic acid-containing structure and a bisdehydroalanine-tail precursor unit. They then elaborated the
ishments of chemistry professor K. C Nicolaou and coworkers at Bisdehydroalanine tail Scripps Research Institute and the University of California, San /Η 8 Diego [Angew. Chem. Int. Ed., 43, NHo 5087 and 5092 (2004)}. Dehydropiperidine "It's a landmark synthesis and an outstanding achievement by the Nicolaou group," comments senior research fellow Christo pherJ. Moody of the department of chemistry at the University of ^NH H Exeter, in England. Moody's group H0X had earlier synthesized two small er thiopeptide antibiotics, proHN 0 Quinaldic acid 'OH macrocycle mothicin and amythiamicin D. The linchpin of thiostrepton's S Thiostrepton structure is a dehydropiperidine ring that supports a bisdehydroalanine tail and two macrocycles—a 26-membered thia- product to obtain thiostrepton. zoline-containing ring and a A reviewer of the group's two 27-membered quinaldic acid sys papers says the synthesis "is a mas tem. Nicolaou and coworkers cre terpiece that highlights state-ofated the critical dehydropiperi the-art technique and opens the dine ring from simple starting field to meaningful structure-ac materials through a biomimetic tivity and mode-of-action studhetero-Diels-Alder dimerization. ies."-STU B0RMAN
«" M
Λ
'X"i
BUSINESS
Syngenta Prevails In China Patent Infringement Case
S
wiss agrochemicat maker Syngenta has successfully con cluded a lawsuit against a Chinese business group that it ac cused of copying one of its products (C&EN, Aug. 9, page 20). Syngenta had argued that two Jiangsu province companies— Yancheng Luye Chemical and affiliate Yancheng Yongli Chemi cal—were illegally producing and selling thiamethoxam, a patented Syngenta insecticide that controls sucking pests. Syn genta demanded that the two companies cease their illegal pro duction and promotion of thiamethoxam, agree not to repeat the violation, publicly apologize, pay Syngenta the maximum com pensation allowed under the law, and bear court fees. Under a court-sponsored settlement between the two parties, Syngenta got all it wanted except for the amount of compensa tion, which did not equal the maximum penalty. "It did not make
HTTP://WWW.CEN-ONLINE.ORG
any commercial sense to pursue the case further," says Susan Zhang, Syngenta's Shanghai-based spokeswoman. The case was handled by a court in Nanjing that has special expertise in intel lectual property cases. Syngenta got much more out of the Chinese legal system than most foreign companies have. Among several notorious exam ples, Toyota had argued in a Beijing court last year that a local manufacturer was infringing its trademark by producing cars bearing a logo similar to Toyota's. The court ruled last Novem ber that Toyota's logo was worthless in China because it was not wetl known. Syngenta says it has invested some $150 million in China and that it employs more than 400 people in the country through joint ventures and its own operations.-JEAN-FRANÇOIS TREMBLAY
C & E N / S E P T E M B E R 2 7 , 2004
7
