SYNTHESIS OF AN ARACHIDONIC ACID ANALOG. Arachidonic Acid Cascade The biological actions of arachidonic acid have essentially been attributed to the conversion.

SYNTHESIS OF AN ARACHIDONIC ACID ANALOG

I n ten siv e P ro g ram 31388-I C -11-2005-1-G R -E R A SM U S-I P U C -1

SY N A PS: Synthesis and R etrosynthesis in the C hem istry

o f N a t u r a l P r o d u c t s

N A T U R A L PR O D U C T C H E M I ST R Y

M o d u le 2

R etrosynthetic A pproaches T ow ards the Synthesis of N atural Products

P r o f . H . E . K ater in o p o u lo s

E d u catio n , A u d io v isu al & C u l tu re E xecu tiv e A gen cy

Arachidonic Acid Cascade

• The biological actions of arachidonic acid have essentially been attributed to the conversion of this substrate to a number of metabolites. The release of these lipid mediators varies considerably and depends to a large extent on the specific cell which is activated. Often several cells may interact to produce these lipid mediators by sharing the substrate and/or enzymes responsible for metabolite formation

• There is now considerable evidence to suggest that metabolites of the arachidonic acid cascade, namely, prostanoids, leukotrienes and lipoxins play a substantial role in the different phases of inflammation.

Arachidonic Acid Cascade• A series of enzymatic pathways, namely, cyclooxygenases

(COX1, COX2) and lipoxygenases are responsible for the formation of numerous lipid mediators known as eicosanoids. The former enzymes are responsible for the formation of prostaglandins and thromboxanes whereas the lipoxygenases transform arachidonic acid to the leukotrienes. The dual lipoxygenation of arachidonic acid by either the 15-lipoxygenase and the 5-lipoxygenase or the 12-lipoxygenase and the 5-lipoxygenase produce eicosanoids known as lipoxins.

• Prostaglandins are involved in fever, inflammation, and pain, and thromboxanes, help regulate blood vessel tone, platelet aggregation, and clot formation.

• Aspirin works by irreversibly disabling the COX enzymes so that they can no longer produce prostaglandins and thromboxanes.





Lindlar reduction would convert the triple bonds to cis-double in a chemoselective way

Lindlar reduction would convert the triple bonds to cis-double in a chemoselective way


The enediyne could be made by the coupling of an acetylenic anion and a tosylate in a SN2 reaction


The terminal alkyne may be prepared by a SN2 reaction of a protected acetylene anion with an iodide. Notice that the protective group in the iodide is an ortho ester that is stable in extreme basic conditions


The ortho ester is prepared by the reaction of a nitrile with gaseous HCL in absolute methanol

FGI

Pinner reactionPinner reaction

The Pinner reaction is an organic reaction of a nitrile with an alcohol under acid catalysis for instance hydrochloric acid. The product formed is the hydrochloric acid salt of an imino ester or an alkyl imidate, which sometimes is called a Pinner salt. The reaction is a sequence of nucleophilic additions.

These salts can react with an excess of alcohol to form the ortho-ester RC(OR)3, with ammonia or an amine to form an amidine or with water to form an ester.

Pinner reactionPinner reaction

C NH2 Cl

R

OR'

R'OH

C

NH3 Cl

R

OR'

O

R'

HCl (g)

R'OH

HCl (g)R C

OR'

OR'

OR'


The tosylate is made from the corresponding alcohol and the eneyne-ol is the result of a coupling of propargyl alcohol with a vinyl bromide

FGI

Sonogashira ReactionSonogashira Reaction

SYNTHESIS OF AN ARACHIDONIC ACID ANALOG. Arachidonic Acid Cascade The biological actions of arachidonic acid have essentially been attributed to the conversion.

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