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Macrolides : chemistry and progress towards a catalytic antibody

University of British Columbia

As part of a continuing study examining the chemistry and conformational behaviour of keto 13-tetradecanolides, 11 -oxo- 13-tetradecanolide (24) was synthesized. In the preparation of the acyclic precursor, optimal yields were obtained when the C-11 ketone was protected until the macrocyclic ring had been formed. Otherwise, a protected β-hydroxy group was eliminated under both acidic and basic conditions. The cyclization was accomplished via a trichlorobenzoyl chloride intermediate. Reduction of 24 using lithium tri-sec-butylborohydride (L-Selectride) gave the (11R* , 13S*)isomer of 49 in >99.8% diastereoselectivity. The relative stereochemistry of 49 was determined by reduction and conversion of the 1,3-diol to an acetonide for ¹³C NMR analysis. Molecular mechanics calculations were used to determine the possible low energy conformations for compounds 24 and 49. Reduction of 24 from the preferred twist [3434] conformations would be expected to give rise to product 49 as is indeed observed. The calculations also predicted ¹H NMR coupling constants in good agreement with the observed values for both 24 and 49. [chemical compound diagrams] As part of an effort to develop a catalytic antibody for the synthesis of macrocyclic lactones, polyclonal antibodies against the phosphonate hapten 130 were raised. These antibodies demonstrated hapten-specific binding, but they did not catalyze the lactonization of a corresponding hydroxy ester substrate under the conditions examined. [chemical compound diagrams]

Thesis/Dissertation

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2009-06-11

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http://hdl.handle.net/2429/8971

Chemistry

University of British Columbia

UBCV

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