Synthesis of leukotrienes via organoiron complexes

Chunlin Tao, Marquette University


Leukotrienes, oxygenated metabolites of arachidonic acid, serve as important regulators and mediators of cell functions. Substantial evidence has indicated that leukotrienes can cause vascular permeability, modulate the inflammatory pain reaction and are important in such immediate hypersensitive reactions as human asthma. This study will focus on the two synthetic challenges existing in the leukotriene structure--(1) the stereospecific introduction of an allylic alcohol functionality and (2) the cis-divinylmethane functionality via organoiron complexes. Model studies for the construction of allylic alcohol functionality have followed two different methods. The first is a hetero Diels-Alder reaction of (sorbaldehyde)-Fe(CO)$\sb3$ and diene 107 to diastereoselectively form two separable dihydropyrones. The relative stereochemistry of one of these products is unambiguously established by a X-ray analysis. A study of the diastereoselectivity of the cycloaddition is undertaken. The further elaboration of the dihydropyrones gives the lactol 116, a useful synthon for the synthesis of LTB$\sb4,$ HETEs and Macrolactin-A. The alternative method is the reaction of dienal-Fe(CO)$\sb3$ complex 157 with lithio OBO orthoester to give two diastereomeric 5-hydroxy ester derivatives. Applying these two procedures, the total synthesis of racemic 5-HETE methyl ester and 5-HETE lactone are completed. The stereospecific preparation of the cis-divinylmethane functionality is accomplished by using the regiospecific addition of an alkynyl cuprate to pentadienyl-Fe(CO)$\sb3$(+1) cation, followed by semihydrogenation. The total synthesis of optically active 5-HETE methyl ester utilized the optically active 64, resolved by ephedrine, as starting material. The introduction of allylic alcohol functionality is established by the reaction of the complexed aldehyde 145 with lithio OBO orthoester, followed by hydrolysis and transesterification, to enantioselectively afford the two optical pure 5-HETE methyl esters in the same sequence. The optical purity of the intermediates and products is monitored by using derivatives or by $\sp1$H NMR analysis with chiral shift reagents. Thus it is demonstrated that a single adjunct, the Fe(CO)$\sb3$ moiety, addressed the two synthetic challenges present in the leukotrienes. The application of the iron complexes outlined above has developed new methods of synthesizing leukotrienes and their analogs.

Recommended Citation

Tao, Chunlin, "Synthesis of leukotrienes via organoiron complexes" (1992). Dissertations (1962 - 2010) Access via Proquest Digital Dissertations. AAI9306004.